title: Analysis of chromatin-state plasticity identifies cell-type-specific regulators of H3K27me3 patterns.
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.
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Heath, Boston, MA 02215.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
mesh_terms: D020816:Amino Acid Motifs; D019540:Area Under Curve; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D019295:Computational Biology; D018899:CpG Islands; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000166:cytology; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006410:Hematopoiesis; D006657:Histones / Q000737:chemistry*; D006801:Humans; D063146:Polycomb-Group Proteins / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C111977:GFI1B protein, human; C067143:TAL1 protein, human
keywords: hematopoiesis; histone modifications; motifs; polycomb