Sin3a associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis.

Haematologica

PubMedID: 24763403

Heideman MR, Lancini C, Proost N, Yanover E, Jacobs H, Dannenberg JH. Sin3a associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis. Haematologica. 2014;.
Class I histone deacetylases, HDACs, are critical regulators of gene transcription by erasing lysine acetylation. Targeting HDACs using relative non-specific small molecule inhibitors, HDACi, is of major interest in treating cancer, neurological disorders and AIDS. Harnessing the therapeutic potential of HDACi requires full knowledge of individual HDACs in vivo. As hematological malignancies show increased sensitivity towards HDACi we targeted deletion of class I Hdac1 and Hdac2 to hematopoietic cell lineages. Here, we show that Hdac1 and Hdac2 collectively control hematopoietic stem cell homeostasis, in a cell-autonomous fashion. Simultaneous loss of Hdac1 and Hdac2 resulted in loss of hematopoietic stem cells and consequently bone marrow failure. Bone-marrow specific deletion of Sin3a, a major Hdac1/2 co-repressor, pheno-copied loss of Hdac1 and Hdac2 indicating that Sin3a associated HDAC1/2-activity is essential for hematopoietic stem cell homeostasis. Although Hdac1 and Hdac2 show compensatory and overlapping functions in hematopoiesis, mice expressing mono-allelic Hdac1 or Hdac2 revealed that Hdac1 and Hdac2 contribute differentially to the development of specific hematopoietic lineages.