HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition

Abstract

SummaryThe first hematopoietic stem and progenitor cells are generated during development from hemogenic endothelium (HE) through trans-differentiation. The molecular mechanisms underlying this endothelial-to-hematopoietic transition (EHT) remain poorly understood. Here, we explored the role of the epigenetic regulators HDAC1 and HDAC2 in the emergence of these first blood cells in vitro and in vivo. Loss of either of these epigenetic silencers through conditional genetic deletion reduced hematopoietic transition from HE, while combined deletion was incompatible with blood generation. We investigated the molecular basis of HDAC1 and HDAC2 requirement and identified TGF-β signaling as one of the pathways controlled by HDAC1 and HDAC2. Accordingly, we experimentally demonstrated that activation of this pathway in HE cells reinforces hematopoietic development. Altogether, our results establish that HDAC1 and HDAC2 modulate TGF-β signaling and suggest that stimulation of this pathway in HE cells would be beneficial for production of hematopoietic cells for regenerative therapies.

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts

“…Their ubiquitous expression, incorporation into similar recruitment complexes, deacetylase activity toward common substrates, and high homology all suggest that HDAC1 and HDAC2 are largely redundant and can compensate for a functional loss of the other. Indeed, mice exhibiting tissue-specific inactivation of Hdac1 or Hdac2 in epidermis 17 , B cells 40 , T cells 41 , cardiomyocytes 31 , endothelial cells 42 , neuronal precursors 43 , neural crest 44 , smooth muscle 45 , and oligodendrocytes 46 , all do not exhibit an obvious phenotypic defect, whereas loss of both Hdac1 and Hdac2 results in severe phenotypes in these tissues 47 . However, in mice, global deletion of Hdac1 results in embryonic lethality at midgestation 48 , which is an effect not observed in mice lacking Hdac2, indicating that HDAC1 and HDAC2 exhibit at least some distinct biological functions.…”

MicroRNA-455-3p mediates GATA3 tumor suppression in mammary epithelial cells by inhibiting TGF-β signaling

“…The ␦EF1 family proteins, namely ␦EF1 (ZEB1) and SIP1 (ZEB2), act as EMT transcription factors and are activated by TGF-␤ signaling (37). Meanwhile, the epigenetic modifier HDAC2 is up-regulated by TGF-␤ signaling during endothelial-to-hematopoietic transition (38), and TGF-␤ also activates HDAC2 in the kidneys (39). We used the public algorithm TargetScan (http://www.targetscan.org/vert_72/) 3 (82) and identified the putative miR-455-3p-binding sites of these three targets, which were all conserved among Sus scrofa, Canis familiaris, Oryctolagus cuniculus, and Homo sapiens.…”

“…Moreover, the chromatin remodeler HDAC2, which is a subunit of the NuRD complex, acts as a corepressor to repress the transcription of E-cadherin and miR-200 and regulate cancer metastasis (65)(66)(67). In collaboration with HDAC1, HDAC2 can also modulate TGF-␤ signaling and promote hematopoiesis in the hemogenic endothelium (38). Thus, the suppression of Smad2, ZEB1, and HDAC2 by the GATA3/miR-455-3p axis is of particular significance.…”

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

“…Transfection of these miRs into CAFs inhibits TGF-β activation and their secretion of IL-8 and FGF, decreasing tumor growth in murine models [ 173 , 174 , 175 ]. Another strategy is to use a histone deacetylase (HDAC) inhibitor such as scriptaid, which acts as a repressor of TGF-β activity [ 176 ]. In a murine melanoma model, scriptaid inhibits the activation of α-SMA+ and COL1+ CAFs by repressing TGF-β signaling and inhibiting ECM production and tumor invasion in a 3D model of tumor/CAFs, and delaying tumor growth in vivo in murine model [ 177 ].…”