Stem/Early Progenitor Cell Commitment is Directed by Hydroxymethylation at Gene Regulatory Regions During Erythropoiesis

hydroxymethylation stem cells epigenetics

Hematopoietic stem cells (HSCs) are rare bone marrow cells that have self-renewal capability and are multipotent. Upon differentiation, HSCs become progressively lineage-committed and give rise to different mature blood cells. This process involves extrinsic and intrinsic signals that are strongly influenced by the stem cell microenvironment.  Furthermore, differentiation involves silencing of self-renewal genes and induction of a specific transcriptional program.

It is not known how epigenetic modifications influences stem cell differentiation and commitment and what specific role these modifications may play. Until the recent discovery of 5-hmC, it was believed that 5-mC was the only DNA base modification. 5-hydroxymethyl cytosine (5-hmC) is a hydroxylated and methylated form of cytosine, generated by the oxidation of 5-mC. This reaction is mediated by the ten-eleven translocation (TET) family of 5-mC hydroxylases. The TET proteins have been shown to function in transcriptional activation and repression.

The broader functions of 5-hmC and DNA hydroxymethylation in epigenetics are still unclear today. However, a line of evidence does show that 5-hmC is predominately located within gene promoter regions and is associated with transcriptionally activated genes and plays a role in DNA demethylation, chromatin remodeling, and brain-specific gene regulation. Because of the presence of 5-hmC in DNA with unclear functions in gene regulation and the discovery of the enzymes that produce 5-hmC, it is considered rather important to know the distribution of this base in different cell types and in different compartments of the genome of mammals.

Researchers at the University of Chicago analyzed the dynamic changes of 5-hmC during human stem/early progenitor cell commitment to the erythroid lineage and during subsequent differentiation. Using a replicative primary human hematopoietic stem/progenitor CD34+ cell differentiation system, the authors identified dynamic changes of 5-hmC during stem cell commitment and differentiation to the erythroid lineage. Their results contribute to our understanding of the functional role epigenetic modifications play in gene regulation, and stem cell function and differentiation.
Their findings are summarized below:

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  • Total 5-hmC levels increased during cell commitment followed by a dramatic decrease throughout subsequent differentiation.
  • A strong correlation was observed between loci that gained 5-hmC and erythroid transcription factor binding suggesting 5-hmC as a positive regulator of transcription factor function.
  • Genomic regions that gained 5-hmC correlate with activating histone marks
  • TET2 deficiency disrupts 5-hmC patterns and impairs erythroid differentiation

Source: Read more about their findings and get all of the details here: Madzo et al, Hydroxymethylation at Gene Regulatory Regions Directs Stem/Early Progenitor Cell Commitment during Erythropoiesis, Cell Reports (2014), http://dx.doi.org/10.1016/j.celrep.2013.11.044

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