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A. Gating strategy applied for flow cytometry analysis of NK cell panel. Phenotype of NK cell (CD56dim CD16+ ) activation was quantified using expression of cell surface markers CD69, CD107a, CD45RA, and CD45RO based on the indicated gates. B. NK cell frequency before and after the treatment analyzed in PBMCs from 18 patient samples and grouped according long-and short-survivors. C. Frequency of NK cells expressing cell surface activation markers CD69, CD107a, and CD45RA and CD45RO measured in short-and long-survival groups before and after the treatment.

Specific genes sequenced in bone marrow mononuclear cells.

Isolation and DNA extraction of bone marrow cell populations; Targeted DNA sequencing; Peripheral blood mononuclear cell (PBMC) staining and flow cytometry analysis

Purpose:We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA.Patients and Methods:We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA (“refractory”) or progressing after a response (“relapsed”) with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginning with guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival.Results:Thirty-three patients, median age 73 (range 54–85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33% [95% confidence interval (CI), 19%–52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5–25.3) months.Conclusions:Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.

Non–small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, with roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely and successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic misregulation during tumorigenesis and metastasis, including widespread changes in DNA methylation and histone modifications. To better understand the role of altered DNA methylation in NSCLC metastasis to the brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation status of normal lung, primary lung tumor, and brain metastasis samples. The variation in methylation was similar during metastatic spread and primary tumorigenesis but less coordinated across genomic features during metastasis. The greatest recurrent changes during metastatic progression were methylation gains in DNA methylation valleys (DMV) harboring the constitutive heterochromatin mark H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1. In a lymph node–derived cancer cell line, EZH2 binding within DMVs was lost, accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of the differentially methylated region–associated DMVs harbored developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression. The characterization of epigenetic changes during NSCLC brain metastasis identified recurrent methylation patterns that may be prognostic biomarkers and contributors to disease progression. Significance: Altered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments.

Non–small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, with roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely and successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic misregulation during tumorigenesis and metastasis, including widespread changes in DNA methylation and histone modifications. To better understand the role of altered DNA methylation in NSCLC metastasis to the brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation status of normal lung, primary lung tumor, and brain metastasis samples. The variation in methylation was similar during metastatic spread and primary tumorigenesis but less coordinated across genomic features during metastasis. The greatest recurrent changes during metastatic progression were methylation gains in DNA methylation valleys (DMV) harboring the constitutive heterochromatin mark H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1. In a lymph node–derived cancer cell line, EZH2 binding within DMVs was lost, accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of the differentially methylated region–associated DMVs harbored developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression. The characterization of epigenetic changes during NSCLC brain metastasis identified recurrent methylation patterns that may be prognostic biomarkers and contributors to disease progression.Significance:Altered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments.

Supplementary Table from Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis

Supplementary Figure from Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis

BackgroundZebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.ResultsWe chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validatealx4aas a necessary and sufficient transcription factor for iridophore differentiation and present evidence onalx4a’s potential regulatory role in guanine synthesis pathway.ConclusionsPigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specificalx4atranscription factor.

Background Zebrafish can faithfully regenerate injured fins through the formation of a blastema, a mass of proliferative cells that can grow and develop into the lost body part. After amputation, various cell types contribute to blastema formation, where each cell type retains fate restriction and exclusively contributes to regeneration of its own lineage. Epigenetic changes that are associated with lineage restriction during regeneration remain underexplored. Results We produce epigenome maps, including DNA methylation and chromatin accessibility, as well as transcriptomes, of osteoblasts and other cells in uninjured and regenerating fins. This effort reveals regeneration as a process of highly dynamic and orchestrated transcriptomic and chromatin accessibility changes, coupled with stably maintained lineage-specific DNA methylation. The epigenetic signatures also reveal many novel regeneration-specific enhancers, which are experimentally validated. Regulatory networks important for regeneration are constructed through integrative analysis of the epigenome map, and a knockout of a predicted upstream regulator disrupts normal regeneration, validating our prediction. Conclusion Our study shows that lineage-specific DNA methylation signatures are stably maintained during regeneration, and regeneration enhancers are preset as hypomethylated before injury. In contrast, chromatin accessibility is dynamically changed during regeneration. Many enhancers driving regeneration gene expression as well as upstream regulators of regeneration are identified and validated through integrative epigenome analysis.

Transposable elements (TEs) are an abundant and rich genetic resource of regulatory sequences1–3. Cryptic regulatory elements within TEs can be epigenetically reactivated in cancer to influence oncogenesis in a process termed onco-exaptation4. However, the prevalence and impact of TE onco-exaptation events across cancer types are poorly characterized. Here, we analyzed 7,769 tumors and 625 normal datasets from 15 cancer types, identifying 129 TE cryptic promoter activation events involving 106 oncogenes across 3,864 tumors. Furthermore, we interrogated the AluJb-LIN28B candidate: the genetic deletion of the TE eliminated oncogene expression, while dynamic DNA methylation modulated promoter activity, illustrating the necessity and sufficiency of a TE for oncogene activation. Collectively, our results characterize the global profile of TE onco-exaptation and highlight this prevalent phenomenon as an important mechanism for promiscuous oncogene activation and ultimately tumorigenesis.

Large-scale sequencing efforts of human cancers have identified recurrent mutations and deletions in a variety of chromatin-regulating proteins that modulate DNA methylation, histone modifications, and nucleosome positioning. The dysregulation of histone H3 lysine 36 (H3K36) methyltransferase, SETD2, through transcriptional or genetic aberrations is associated with worse clinical outcomes and metastasis in kidney cancer. Limited targeted therapeutic interventions are available for aggressive SETD2-mutant ccRCC tumors. Here, we reveal that kidney cancer cells displaying diminished H3K36 trimethylation levels, a consequence of SETD2 deficiency, show increased sensitivity of anti-tumor effects to DNA hypomethylating agent (HMA). We discovered that HMA treatment induced stronger viral mimicry activation and immune upregulation, which is potentiated by higher transposable element (TE) expression in SETD2-mutant cancer cells. Mechanistically, we provide evidence that substantial number of the HMA-induced TE expression is a consequence of mis-splicing, which is associated deficient in slicing in SETD2-loss content along with rapid gain of H3K9me3 across exons. These all suggested HMA could turn immune-cold tumor to immune-hot tumor and sensitize tumors to immune therapy. Then we performed in vivo assay in immune competent mice. Indeed, SETD2 deficient tumors were extremely sensitive to combination treatment of HMA and immune checkpoint inhibitor. Our finding provides one of the first preclinical and in vivo evidence that demonstrates the SETD2 dysregulation can be an epigenetic therapeutic target in ccRCC, especially in combination with immune checkpoint inhibitors, for future clinical trials. Citation Format: Hong-Tao Li, Hyo Sik Jang, Krizia Rohena-Rivera, Hemant Gujar, Minmin Liu, Justin Kulchycki, Xinyi Zhou, Shuqing Zhao, Peter Jones, Neil Bhowmick, Gangning Liang. Loss of SETD2 sensitizes kidney cancer cells to DNA methylation inhibitors by inducing viral mimicry and RNA mis-splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3618.

Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed.Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time.TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

BackgroundTransposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed.ResultsHere, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time.ConclusionsTEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

Transposable elements (TEs) represent close to half of the genome and are generally disregarded in genomic studies due to their silencing in somatic tissues and difficulty in mapping to their repetitive sequences. Recent studies have revealed that epigenetic dysregulation in cancer can unlock the regulatory potential of transposable elements (TEs), and they can play an important role in cancer progression and oncogenesis. One important consequence of this phenomenon is the pervasive activation of TEs' intrinsic promoters, which leads to generation of thousands of unique transcripts. Many of these transcripts splice into downstream genes and lead to the generation of TE-gene chimeric transcripts. These transcripts can alter the main reading frame of the original transcript to generate unique isoforms of the target gene or generate novel out-of-frame peptides that could be therapeutic targets. In this study, we analyzed the transcriptomes of 11,092 samples from 33 TCGA cancer types and 675 cancer cell lines to comprehensively profile all TE-gene fusion transcripts. Using somatic tissues from FANTOM5 and GTEx, we filtered these transcripts for tumor-specificity and discovered 2,642 tumor-specific TE-gene transcripts that promiscuously occur in nearly all TCGA tumor samples. Computational prediction of reading frames of these transcripts identified 1,202 candidates with the potential to generate tumor-specific TE-derived antigens (TS-TEAs). We further analyzed tumor mass spectrometry data from breast adenocarcinoma and ovarian cancer and confirmed that unique peptide sequences from TS-TEAs could be detected. In addition, we performed HLA-pulldown mass spectrometry and confirmed that TS-TEAs are presented on the cell surface in cancer cell lines. Given that these antigens are highly shared within and across cancer types, we assessed their potential to generate universal antigen-based therapies. Optimal combinations of 5, 10, and 20 TS-TEAs could generate unique peptides that bind to patient-specific HLA alleles for 39.2%, 50.8%, and 60.8% of all TCGA tumors respectively. Lastly, we highlight the tumor-specific membrane proteins transcribed from TE-exapted promoters that can potentially expose novel epitopes on the extracellular surface of cancer cells. These can be valuable targets of CAR-T or alternative antibody-based therapies. In conclusion, we showcase the high prevalence of TE-derived promoter activation in cancer and suggest multiple avenues by which this phenomenon can be targeted therapeutically. Citation Format: Nakul M. Shah, Hyo Sik Jang, Ju Heon Maeng, Shin-Cheng Tzeng, Angela Wu, Changxu Fan, Noah L. Basri, Benjamin Katz, Daofeng Li, Xiaoyun Xing, Bradley S. Evans, Ting Wang. Transposable elements are an abundant and pan-cancer source of shared tumor-specific antigens and membrane targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2225.

Introduction: We report the results of a phase II trial testing the hypothesis that adding the hypomethylating agent G to the PDL1 inhibitor A in patients with mUC who developed primary or acquired resistance to checkpoint blockade (CB) will overcome this resistance by (1) eliciting viral mimicry in the tumor tissue to potentiate and reinvigorate anti-tumor immunity, (2) epigenetic reprogramming of T lymphocytes to overcome exhaustion. Methods: Pts with mUC resistant to CB accrued at 3 centers were treated with G 45mg/m2 daily days 1-5 every 6 wks and A 1200mg every 3 wks. After initial safety lead in with 6 patients, trial was designed to add 37 additional patients. The primary endpoint was ORR. Correlative analyses included analysis of peripheral blood T cells and tumor tissue collected at baseline and once during treatment. Results: 21 pts were enrolled. 20 pts were evaluable for response. Best response was PD (16), SD (4). 10 patients progressed clinically prompting earlier than scheduled (12 wk) imaging. Four pts exhibited a “hyperprogression” phenotype exhibiting rapid acceleration of tumor growth rate starting with initiation of therapy. At presepcified interim analysis it was determined that the trial would not meet its primary endpoint and it closed early. Median PFS 2.6 mo, median OS 8 mo. The 4 patients with SD maintained that status for median 13 months (range 9-15 mo). Global DNA methylome and transcriptome profiles from pre- and post-treatment tumor samples revealed a lack of transposable element-induced viral mimicry activation, which correlated with minimal DNA demethylation being induced in the tumors. Of note, flow cytometry-based immune profiling of peripheral blood from patients suggests a correlation between increased progression-free survival (PFS) with 1) lower expression of DNAM-1 on mature NK cells and 2) lower expression of CD39 on CD8+ effector T cells at time of inclusion on the trial. Conclusions: While no responses were seen, both prolonged SD and hyperprogression were seen. Further tissue and peripheral blood based analyses are ongoing to elucidate the biological determinates of this dichotomy. Citation Format: Elizabeth R. Plimack, Kerry Campbell, Jean-Pierre J. Issa, Noah M. Hahn, David I. Quinn, Hyo Sik Jang, Galen Hostetter, Peter W. Nichols, Woonbok Chung, Jozef Madzo, Hitoshi Ohtani, Hui Shen, Toshinori Hinoue, Stephen B. Baylin, Peter A. Jones. A Phase II trial of guadecitabine (G) plus atezolizumab (A) in patients with metastatic urothelial carcinoma (UC) progressing after initial checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT121.

Background Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns. Results Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors. Conclusions Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites. Electronic supplementary material The online version of this article (10.1186/s12864-017-4115-6) contains supplementary material, which is available to authorized users.

A deep learning–based model predicts single-CpG hydroxy/methylation levels from cheaper orthogonal epigenetic profiling methods., Increased appreciation of 5-hydroxymethylcytosine (5hmC) as a stable epigenetic mark, which defines cell identity and disease progress, has engendered a need for cost-effective, but high-resolution, 5hmC mapping technology. Current enrichment-based technologies provide cheap but low-resolution and relative enrichment of 5hmC levels, while single-base resolution methods can be prohibitively expensive to scale up to large experiments. To address this problem, we developed a deep learning–based method, “DeepH&M,” which integrates enrichment and restriction enzyme sequencing methods to simultaneously estimate absolute hydroxymethylation and methylation levels at single-CpG resolution. Using 7-week-old mouse cerebellum data for training the DeepH&M model, we demonstrated that the 5hmC and 5mC levels predicted by DeepH&M were in high concordance with whole-genome bisulfite–based approaches. The DeepH&M model can be applied to 7-week-old frontal cortex and 79-week-old cerebellum, revealing the robust generalizability of this method to other tissues from various biological time points.

Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single-cell eukaryotes to human, comparative analyses are still relatively few and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. We review here the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site (TFBS) turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.

In the version of this article initially published, grant PF-17-201-01-TBG from the American Cancer Society to author Erica C. Pehrsson was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.

Transcription start site (TSS) evolution remains largely undescribed in Drosophila, likely due to limited annotations in non-melanogaster species. In this study, we introduce a concise new method that selectively sequences from the 5'-end of mRNA and used it to identify TSS in four Drosophila species, including Drosophila melanogaster, D. simulans, D. sechellia, and D. pseudoobscura. For verification, we compared our results in D. melanogaster with known annotations, published 5'-rapid amplification of cDNA ends data, and with RNAseq from the same mRNA pool. Then, we paired 2,849 D. melanogaster TSS with its closest equivalent TSS in each species (likely to be its true ortholog) using the available multiple sequence alignments. Most of the D. melanogaster TSSs were successfully paired with an ortholog in each species (83%, 86%, and 55% for D. simulans, D. sechellia, and D. pseudoobscura, respectively). On the basis of the number and distribution of reads mapped at each TSS, we also estimated promoter-specific expression (PSE) and TSS peak shape, respectively. Among paired TSS orthologs, the location and promoter activity were largely conserved. TSS location appears important as PSE, and TSS peak shape was more frequently divergent among TSS that had moved. Unpaired TSS were surprisingly common in D. pseudoobscura. An increased mutation rate upstream of TSS might explain this pattern. We found an enrichment of ribosomal protein genes among diverged TSS, suggesting that TSS evolution is not uniform across the genome.

This paper proposes super-resolution reconstruction algorithm for image enhancement. Super-resolution reconstruction algorithms reconstruct a high-resolution image from multi-frame low-resolution images of a scene. Conventional super- resolution reconstruction algorithms are iterative back-projection(IBP), robust super-resolution(RS)method and standard Papoulis-Gerchberg(PG)method. However, traditional methods have some problems such as rotation and ringing. So, this paper proposes modified algorithm to improve the problem. Experimental results show that this proposed algorithm solve the problem. As a result, the proposed method showed an increase in the PSNR for traditional super-resolution reconstruction algorithms.

Chlamydomonas reinhardtii is a model system for studying cilia, photosynthesis, and other core features of eukaryotes, and is also an emerging source of biofuels. Despite its importance to basic and applied biological research, the level and pattern of genetic variation in this haploid green alga has yet to be characterized on a genome-wide scale. To improve understanding of C. reinhardtii's genetic variability, we generated low coverage whole genome resequencing data for nearly all of the available isolates of this species, which were sampled from a number of sites in North America over the past ∼70 years. Based on the analysis of more than 62,000 single nucleotide polymorphisms, we identified two groups of isolates that represent geographical subpopulations of the species. We also found that measurements of genetic diversity were highly variable throughout the genome, in part due to technical factors. We studied the level and pattern of linkage disequilibrium (LD), and observed one chromosome that exhibits elevated LD. Furthermore, we detected widespread evidence of recombination across the genome, which implies that outcrossing occurs in natural populations of this species. In summary, our study provides multiple insights into the sequence diversity of C. reinhardtii that will be useful to future studies of natural genetic variation in this organism.