Dpy30 is critical for maintaining the identity and function of adult hematopoietic stem cells

Abstract

Jiang et al. generated Dpy30 conditional knockout mice to determine what role Dpy30 and its associated H3K4 methylation may play in the fate determination of tissue-specific stem cells such as HSCs.

Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis

“…Within the hematopoietic system, conditional deletion of Setd1a , Cxxc1 , or Dpy30 results in the accumulation of short-term HSCs and multi-potent progenitors but these cells do not engraft secondary recipients in the case of Setd1a and Dpy30 knockouts [62**,63]. These data suggest that the loss of Setd1a -mediated H3K4 modifications may dominate the phenotype in the Dpy30 knockout, but more detailed side-by-side comparisons will be required to determine this.…”

“…These data suggest that the loss of Setd1a -mediated H3K4 modifications may dominate the phenotype in the Dpy30 knockout, but more detailed side-by-side comparisons will be required to determine this. Genes deregulated in HSPCs are very distinct between the Dpy30/Setd1a as compared to Mll1 and Mll2 knockouts, further underscoring the unique functions of each of the HMTs in the hematopoietic system ([62**,63], Waskow C, personal communication, TU Dresden).…”

SET/MLL family proteins in hematopoiesis and leukemia

“…In contrast to CFP1 loss, the overall levels of H3K4me3/2/1 were significantly reduced in bone-marrow HSPCs. However, Mx1-Cre-mediated deletion resulted in bone-marrow failure and animal death in the same time frame as CFP1 loss and a significant accumulation of LT-HSCs and ST-HSCs in Dpy30−/− bone marrow or cells in primary recipient bone marrow [78]. In this conditional knockout, however, neither abnormal cell proliferation nor decreased HSPC apoptosis were observed.…”

“…For example, a comparison of the CFP1, DPY30, and SETd1A loss-of-function models discussed above suggests that the loss of any of these proteins results in overlapping phenotypes in HSPCs. One might have predicted that Dpy30−/− bone marrow would exhibit a phenotype representing the loss of all 6 SET/MLL family members, but instead this knockout resembles most the SETd1A knockout ( [40,72,78], Claudia Waskow, personal communication). These observations are consistent with the fact that the HMT activity of MLL1 is not required for its role in HSPCs, thus may not be affected by DPY30 loss [47].…”

“…Rather, the authors observe a block in HSC differentiation based on the inability of Dpy30−/− bone marrow to yield differentiated colonies in vitro or to differentiate posttransplant in vivo. Furthermore, despite the accumulation in HSCs in conditionally Dpy30−/− bone marrow, in a chimeric setting, these cells fail to contribute long term to even the HSPC pool [78]. Gene expression studies reveal downregulation of HSC genes by gene-set enrichment analysis, but the identity of those genes is very distinct from those deregulated in the Mll1 knockout, which is the most comparably analyzed SET/MLL family member.…”