Epigenetic regulation of hematopoiesis by DNA methylation

Abstract

During embryonic development, cell type-specific transcription factors promote cell identities, while epigenetic modifications are thought to contribute to maintain these cell fates. Our understanding of how genetic and epigenetic modes of regulation work together to establish and maintain cellular identity is still limited, however. Here, we show that DNA methyltransferase 3bb.1 ( dnmt3bb.1) is essential for maintenance of hematopoietic stem and progenitor cell (HSPC) fate as part of an early Notch-runx1-cmyb HSPC specification pathway in the zebrafish. Dnmt3bb.1 is expressed in HSPC downstream from Notch1 and runx1, and loss of Dnmt3bb.1 activity leads to reduced cmyb locus methylation, reduced cmyb expression, and gradual reduction in HSPCs. Ectopic overexpression of dnmt3bb.1 in non-hematopoietic cells is sufficient to methylate the cmyb locus, promote cmyb expression, and promote hematopoietic development. Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs.

DOI: http://dx.doi.org/10.7554/eLife.11813.001

eLife digest

The cells in our blood are constantly being replaced with new cells that are produced by stem cells called hematopoietic stem and progenitor cells (or HSPCs for short). The HSPCs form early on in the development of the embryo and continue in the same role throughout the life of the animal.

A gene called runx1 is required for HSPCs to form, but is not required for these cells to maintain their role (cell identity) in the long term. In mice, this gene is only expressed for a brief period of time as the HSPCs form, and is switched off in the mature stem cells. Another gene called cmyb – which is switched on by runx1 – is also required for HSPCs to form. However, unlike runx1, cmyb continues to be expressed in mature HSPCs and is required to maintain HSPC identity. It is not known how the temporary activation of runx1 causes the long-term expression of cmyb.

One possible explanation is that the cmyb gene may be subject to a process called DNA methylation. This process is carried out by enzymes called DNA methyltransferases and can have long-term effects on the expression of genes by modifying the structure of the DNA that encodes them. Here, Gore et al. investigate the role of a particular DNA methyltransferase in the formation of HSPCs in zebrafish embryos. The experiments show that this enzyme is activated in developing HSPCs in response to an increase in runx1 expression. The loss of this enzyme’s activity reduces both the amount that cmyb is methylated and its level of expression, which results in a gradual decline in the number of HSPCs in zebrafish.

Further experiments show that if the DNA methyltransferase is artificially activated in cells that don’t normally form blood cells, these cells change their identity to do so. This switch is accompanied by methylation of cmyb and an increase in its expression. Gore et al.’s findings reveal that the temporary activation of runx1 triggers the production of an enzyme that methylates cmyb to maintain the identity of HSPCs. Future studies should help to reveal exactly how runx1 promotes DNA methylation, and whether this process can be harnessed to promote HSPC formation for research or medical treatments.

DOI: http://dx.doi.org/10.7554/eLife.11813.002