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Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):E344-53. doi: 10.1073/pnas.1322570111. Epub 2014 Jan 6.

Analysis of chromatin-state plasticity identifies cell-type-specific regulators of H3K27me3 patterns.

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1
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Heath, Boston, MA 02215.

Abstract

Chromatin states are highly cell-type-specific, but the underlying mechanisms for the establishment and maintenance of their genome-wide patterns remain poorly understood. Here we present a computational approach for investigation of chromatin-state plasticity. We applied this approach to investigate an ENCODE ChIP-seq dataset profiling the genome-wide distributions of the H3K27me3 mark in 19 human cell lines. We found that the high plasticity regions (HPRs) can be divided into two functionally and mechanistically distinct subsets, which correspond to CpG island (CGI) proximal or distal regions, respectively. Although the CGI proximal HPRs are typically associated with continuous variation across different cell-types, the distal HPRs are associated with binary-like variations. We developed a computational approach to predict putative cell-type-specific modulators of H3K27me3 patterns and validated the predictions by comparing with public ChIP-seq data. Furthermore, we applied this approach to investigate mechanisms for poised enhancer establishment in primary human erythroid precursors. Importantly, we predicted and experimentally validated that the principal hematopoietic regulator T-cell acute lymphocytic leukemia-1 (TAL1) is involved in regulating H3K27me3 variations in collaboration with the transcription factor growth factor independent 1B (GFI1B), providing fresh insights into the context-specific role of TAL1 in erythropoiesis. Our approach is generally applicable to investigate the regulatory mechanisms of epigenetic pathways in establishing cellular identity.

KEYWORDS:

hematopoiesis; histone modifications; motifs; polycomb

PMID:
24395799
PMCID:
PMC3903219
DOI:
10.1073/pnas.1322570111
[Indexed for MEDLINE]
Free PMC Article
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