Int J Stem Cells.  2016 May;9(1):36-43. 10.15283/ijsc.2016.9.1.36.

Epigenetic Regulation of Hematopoietic Stem Cells

• Sharma S
• Gurudutta

• KMID: 2164159
• DOI: http://doi.org/10.15283/ijsc.2016.9.1.36

Abstract

Hematopoietic stem cells are endowed with a distinct potential to bolster self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. Both hematopoietic stem cells and mature cells have the same genome, but their gene expression is controlled by an additional layer of epigenetics such as DNA methylation and post-translational histone modifications, enabling each cell-type to acquire various forms and functions. Until recently, several studies have largely focussed on the transcription factors andniche factors for the understanding of the molecular mechanisms by which hematopoietic cells replicate and differentiate. Several lines of emerging evidence suggest that epigenetic modifications eventually result in a defined chromatin structure and an "individual" gene expression pattern, which play an essential role in the regulation of hematopoietic stem cell self-renewal and differentiation. Distinct epigenetic marks decide which sets of genes may be expressed and which genes are kept silent. Epigenetic mechanisms are interdependent and ensure lifelong production of blood and bone marrow, thereby contributing to stem cell homeostasis. The epigenetic analysis of hematopoiesis raises the exciting possibility that chromatin structure is dynamic enough for regulated expression of genes. Though controlled chromatin accessibility plays an essential role in maintaining blood homeostasis; mutations in chromatin impacts on the regulation of genes critical to the development of leukemia. In this review, we explored the contribution of epigenetic machinery which has implications for the ramification of molecular details of hematopoietic self-renewal for normal development and underlying events that potentially co-operate to induce leukemia.

Keyword

Epigenetics; Self-renewal; Regulation; Hematopoietic stem cells

MeSH Terms

Bone Marrow
Chromatin
DNA Methylation
Epigenomics*
Gene Expression
Genome
Hematopoiesis
Hematopoietic Stem Cells*
Histones
Homeostasis
Leukemia
Stem Cells
Transcription Factors
Chromatin
Histones
Transcription Factors

Figure

• 

  Fig. 1 Schematic of nucleosome structure. Nucleosomes are the smallest structural unit of chromatin. Nucleosome consists of two copies of each core histone (H2A, H2B, H3 and H4) and ~150 bp DNA. The N-terminal tail of each histone is extruded from the nucleosome. Amino acids in histone tails can be modified by numerous enzymes bringing acetylation, methylation, phosphorylation, ubiquitination and other substitutions, creating a complex ‘bar’ code, which may influence chromatin structure by affecting histone-histone and histone-DNA interactions. Post-translational modifications of histones regulate transcription of genes important for self-renewal and differentiation.

• 

  Fig. 2 Histone modifications: Active genes: Open chromatin structure of transcriptionally active gene with loosely spaced nucleosomes. Acetylation of lysine neutralizes the positive charge, reducing affinity between histone and DNA, which functions as platforms for the recruitment of transcription factors or chromatin remodelers, thus histone modifications directly effects nucleosomal architecture. H3K4me3 is enriched around transcription start sites. H3K4me1 is enriched around enhancers and downstream. H3K27ac is enriched around active enhancers and transcription start sites. Bivalent genes: In undifferentiated stem cells, both H3K4me3 and H3K27me3 (active and inactive marks, respectively) are enriched around transcription start sites on many genes. The multiple coexisting histone modifications are associated with activation and repression. Inactive genes: H3K9me3 is broadly distributed on inactive regions. H3K27me3 and H3K9me3 are usually not colocalized. Proteins associated for transcription silencing are DNMT- DNA methyl-transferase, MBD-Methyl-binding domain, HP-1-Heterochromatin protein and CAF-1-Chromatin assembly factor1.

Reference

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