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We report on the development of an unsupervised algorithm for the genome-wide discovery and analysis of chromatin signatures. Our Chromatin-profile Alignment followed by Tree-clustering algorithm (ChAT) employs dynamic programming of combinatorial histone modification profiles to identify locally similar chromatin sub-regions and provides complementary utility with respect to existing methods. We applied ChAT to genomic maps of 39 histone modifications in human CD4(+) T cells to identify both known and novel chromatin signatures. ChAT was able to detect chromatin signatures previously associated with transcription start sites and enhancers as well as novel signatures associated with a variety of regulatory elements. Promoter-associated signatures discovered with ChAT indicate that complex chromatin signatures, made up of numerous co-located histone modifications, facilitate cell-type specific gene expression. The discovery of novel L1 retrotransposon-associated bivalent chromatin signatures suggests that these elements influence the mono-allelic expression of human genes by shaping the chromatin environment of imprinted genomic regions. Analysis of long gene-associated chromatin signatures point to a role for the H4K20me1 and H3K79me3 histone modifications in transcriptional pause release. The novel chromatin signatures and functional associations uncovered by ChAT underscore the ability of the algorithm to yield novel insight on chromatin-based regulatory mechanisms.

Cellular senescence is associated with global chromatin changes, altered gene expression, and activation of chronic DNA damage signaling. These events ultimately lead to morphological and physiological transformations in primary cells. In this study, we show that chronic DNA damage signals caused by genotoxic stress impact the expression of histones H2A family members and lead to their depletion in the nuclei of senescent human fibroblasts. Our data reinforce the hypothesis that progressive chromatin destabilization may lead to the loss of epigenetic information and impaired cellular function associated with chronic DNA damage upon drug-evoked senescence. We propose that changes in the histone biosynthesis and chromatin assembly may directly contribute to cellular aging. In addition, we also outline the method that allows for quantitative and unbiased measurement of these changes.

Summary: Although some histone modification chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) signals show abrupt peaks across narrow and specific genomic locations, others have diffuse distributions along chromosomes, and their large contiguous enrichment landscapes are better modeled as broad peaks. Here, we present BroadPeak, an algorithm for the identification of such broad peaks from diffuse ChIP-seq datasets. We show that BroadPeak is a linear time algorithm that requires only two parameters, and we validate its performance on real and simulated histone modification ChIP-seq datasets. BroadPeak calls peaks that are highly coincident with both the underlying ChIP-seq tag count distributions and relevant biological features, such as the gene bodies of actively transcribed genes, and it shows superior overall recall and precision of known broad peaks from simulated datasets.Availability: The source code and documentations are available at http://jordan.biology.gatech.edu/page/software/broadpeak/.Contact: king.jordan@biology.gatech.eduSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]