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31 results on '"Lardo, Santana M."'

23. An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

Author

Nmezi, Bruce, Bey, Guillermo Rodriguez, Oranburg, Talia DeFrancesco, Dudnyk, Kseniia, Lardo, Santana M, Herdman, Nathan, Jacko, Anastasia, Rubio, Sandy, Alcocer, Emanuel Loeza, Kofler, Julia, Kim, Dongkyeong, Rankin, Julia, Kivuva, Emma, Gutowski, Nicholas, Schon, Katherine, van den Ameele, Jelle, Chinnery, Patrick F, Sousa, Sérgio B, Palavra, Filipe, Toro, Camilo, Pinto E Vairo, Filippo, Saute, Jonas, Pan, Lisa, Alturkustani, Murad, Hammond, Robert, Gros-Louis, Francois, Gold, Michael, Park, Yungki, Bernard, Geneviève, Raininko, Raili, Zhou, Jian, Hainer, Sarah J, Padiath, Quasar S, Nmezi, Bruce, Bey, Guillermo Rodriguez, Oranburg, Talia DeFrancesco, Dudnyk, Kseniia, Lardo, Santana M, Herdman, Nathan, Jacko, Anastasia, Rubio, Sandy, Alcocer, Emanuel Loeza, Kofler, Julia, Kim, Dongkyeong, Rankin, Julia, Kivuva, Emma, Gutowski, Nicholas, Schon, Katherine, van den Ameele, Jelle, Chinnery, Patrick F, Sousa, Sérgio B, Palavra, Filipe, Toro, Camilo, Pinto E Vairo, Filippo, Saute, Jonas, Pan, Lisa, Alturkustani, Murad, Hammond, Robert, Gros-Louis, Francois, Gold, Michael, Park, Yungki, Bernard, Geneviève, Raininko, Raili, Zhou, Jian, Hainer, Sarah J, and Padiath, Quasar S

Abstract

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene ( LMNB1 ) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

Published
2023
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27. HIRA protects telomeres against R-loop-induced instability in ALT cancer cells

Author

Lynskey, Michelle Lee, Brown, Emily E., Bhargava, Ragini, Wondisford, Anne R., Ouriou, Jean-Baptiste, Freund, Oliver, Bowman, Ray W., Smith, Baylee A., Lardo, Santana M., Schamus-Hayes, Sandra, Hainer, Sarah J., and O’Sullivan, Roderick J.

Abstract

Inactivating mutations in chromatin modifiers, like the α-thalassemia/mental retardation, X-linked (ATRX)-death domain-associated protein (DAXX) chromatin remodeling/histone H3.3 deposition complex, drive the cancer-specific alternative lengthening of telomeres (ALT) pathway. Prior studies revealed that HIRA, another histone H3.3 chaperone, compensates for ATRX-DAXX loss at telomeres to sustain ALT cancer cell survival. How HIRA rescues telomeres from the consequences of ATRX-DAXX deficiency remains unclear. Here, using an assay for transposase-accessible chromatin using sequencing (ATAC-seq) and cleavage under targets and release using nuclease (CUT&RUN), we establish that HIRA-mediated deposition of new H3.3 maintains telomeric chromatin accessibility to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) in ATRX-DAXX-deficient ALT cells. We show that the HIRA-UBN1/UBN2 complex deposits new H3.3 to prevent TERRA R-loop buildup and transcription-replication conflicts (TRCs) at telomeres. Furthermore, HIRA-mediated H3.3 incorporation into telomeric chromatin links productive ALT to the phosphorylation of serine 31, an H3.3-specific amino acid, by Chk1. Therefore, we identify a critical role for HIRA-mediated H3.3 deposition that ensures the survival of ATRX-DAXX-deficient ALT cancer cells.

Published
2024
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28. Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

Author

Xu, Jianquan, primary, Ma, Hongqiang, additional, Ma, Hongbin, additional, Jiang, Wei, additional, Duan, Meihan, additional, Zhao, Shimei, additional, Gao, Chenxi, additional, Hahm, Eun-Ryeong, additional, Lardo, Santana M., additional, Troy, Kris, additional, Sun, Ming, additional, Pai, Reet, additional, Stolz, Donna B, additional, Singh, Shivendra, additional, Brand, Randall E, additional, Hartman, Douglas J., additional, Hu, Jing, additional, Hainer, Sarah J., additional, and Liu, Yang, additional

Published
2019
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29. Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet

Author

Viner, Coby, primary, Ishak, Charles A., additional, Johnson, James, additional, Walker, Nicolas J., additional, Shi, Hui, additional, Sjöberg-Herrera, Marcela K., additional, Shen, Shu Yi, additional, Lardo, Santana M., additional, Adams, David J., additional, Ferguson-Smith, Anne C., additional, De Carvalho, Daniel D., additional, Hainer, Sarah J., additional, Bailey, Timothy L., additional, and Hoffman, Michael M., additional

Published
2016
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30. The ncBAF Complex Regulates Transcription in AML Through H3K27ac Sensing by BRD9.

Author

Klein DC, Lardo SM, and Hainer SJ

Subjects
Humans, Nuclear Proteins genetics, Gene Expression Regulation, Chromatin genetics, Bromodomain Containing Proteins, Transcription Factors genetics, Leukemia, Myeloid, Acute genetics
Abstract

The non-canonical BAF complex (ncBAF) subunit BRD9 is essential for acute myeloid leukemia (AML) cell viability but has an unclear role in leukemogenesis. Because BRD9 is required for ncBAF complex assembly through its DUF3512 domain, precise bromodomain inhibition is necessary to parse the role of BRD9 as a transcriptional regulator from that of a scaffolding protein. To understand the role of BRD9 bromodomain function in regulating AML, we selected a panel of five AML cell lines with distinct driver mutations, disease classifications, and genomic aberrations and subjected these cells to short-term BRD9 bromodomain inhibition. We examined the bromodomain-dependent growth of these cell lines, identifying a dependency in AML cell lines but not HEK293T cells. To define a mechanism through which BRD9 maintains AML cell survival, we examined nascent transcription, chromatin accessibility, and ncBAF complex binding genome-wide after bromodomain inhibition. We identified extensive regulation of transcription by BRD9 bromodomain activity, including repression of myeloid maturation factors and tumor suppressor genes, while standard AML chemotherapy targets were repressed by inhibition of the BRD9 bromodomain. BRD9 bromodomain activity maintained accessible chromatin at both gene promoters and gene-distal putative enhancer regions, in a manner that qualitatively correlated with enrichment of BRD9 binding. Furthermore, we identified reduced chromatin accessibility at GATA, ETS, and AP-1 motifs and increased chromatin accessibility at SNAIL-, HIC-, and TP53-recognized motifs after BRD9 inhibition. These data suggest a role for BRD9 in regulating AML cell differentiation through modulation of accessibility at hematopoietic transcription factor binding sites., Significance: The bromodomain-containing protein BRD9 is essential for AML cell viability, but it is unclear whether this requirement is due to the protein's role as an epigenetic reader. We inhibited this activity and identified altered gene-distal chromatin regulation and transcription consistent with a more mature myeloid cell state., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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31. An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.

Author

Nmezi B, Bey GR, Oranburg TD, Dudnyk K, Lardo SM, Herdman N, Jacko A, Rubio S, Alcocer EL, Kofler J, Kim D, Rankin J, Kivuva E, Gutowski N, Schon K, van den Ameele J, Chinnery PF, Sousa SB, Palavra F, Toro C, Pinto E Vairo F, Saute J, Pan L, Alturkustani M, Hammond R, Gros-Louis F, Gold M, Park Y, Bernard G, Raininko R, Zhou J, Hainer SJ, and Padiath QS

Abstract

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene ( LMNB1 ) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

Published
2023
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