Differential H3K4 Methylation Identifies Developmentally Poised Hematopoietic Genes

Abstract

Throughout development, cell fate decisions are converted into epigenetic information that determines cellular identity. Covalent histone modifications are heritable epigenetic marks and are hypothesized to play a central role in this process. In this report, we assess the concordance of histone H3 lysine 4 dimethylation (H3K4me2) and trimethylation (H3K4me3) on a genome-wide scale in erythroid development by analyzing pluripotent, multipotent, and unipotent cell types. Although H3K4me2 and H3K4me3 are concordant at most genes, multipotential hematopoietic cells have a subset of genes that are differentially methylated (H3K4me2+/me3-). These genes are transcriptionally silent, highly enriched in lineage-specific hematopoietic genes, and uniquely susceptible to differentiation-induced H3K4 demethylation. Self-renewing embryonic stem cells, which restrict H3K4 methylation to genes that contain CpG islands (CGIs), lack H3K4me2+/me3- genes. These data reveal distinct epigenetic regulation of CGI and non-CGI genes during development and indicate an interactive relationship between DNA sequence and differential H3K4 methylation in lineage-specific differentiation.

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

“…4,5 Similarly, the H3K4 methylation status of promoter regions was reported to regulate hematopoietic stem and progenitor multilineage potential and differentiation. [8][9][10] Thus, it is likely that LSD1-kd disturbs hematopoiesis by interfering with the tightly regulated H3K4 methylation status of genes critical for early events in hematopoietic stem and progenitor cell differentiation. Because H3K4 demethylation activity at these promoter regions should be reestablished upon reinstatement of LSD1 expression, we were interested whether normal hematopoiesis returns upon normalization of LSD1 levels.…”

“…2,6,7 The methylation status of the H3K4 and H3K27 residues, composing a so-called bivalent domain, in hematopoietic stem and progenitor cells was shown to be capable of restraining lineage-specific gene expression, while exposing the locus to rapid induction. [8][9][10] Recent in vitro studies have demonstrated that the LSD1 H3K4 demethylating activity is directed to specific genes by the key hematopoietic transcription factors, SCL (also called Tal-1) and Gfi1b. Moreover, in vitro knockdown of LSD1 disturbed hematopoietic differentiation of several cell lines.…”

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

“…Lineage promiscuity in t(8;21) AML K Walter et al silencing (Ooi et al, 2007) and therefore keeps the locus poised for transcription (Orford et al, 2008), whereas H3K27me3 is a hallmark of transcriptional repression mediated by polycomb group complexes (Kohler and Villar, 2008). These data suggest that the CD19 promoter is poised for transcription in KG-1 and epigenetically silenced in HeLa cells, whereby there is no CD19 transcription in either cell line (Supplementary Figure S3c).…”

Emerging Role of the Peroxisome Proliferator-Activated Receptors in Hepatocellular Carcinoma

“…At each juncture, the epigenetic information can be interpreted by cell-type specific transcription factors. Therefore, the idea that the cell-specific distribution of epigenetic marks at enhancers might be responsible for particular signalling output during differentiation is sustained by the presence of H3k4me2 marks at enhancers of developmentally poised haematopoietic genes in multipotent haematopoietic cell line [40].…”

“…As the changes in epigenetic patterns at enhancers depict the cell-type specificity [29,40,61], reprogramming of somatic cells to Induced pluripotent stem cells (iPSCs) would impose the reversion of these changes. The pre-patterning of enhancers in ESCs, derived from the inner cell mass at the blastocyst stage, is likely to occur during the early stage of embryonic development.…”