Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes

Abstract

We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2. Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid–erythroid progenitor cells. In vitro, SMARCD2 interacts with the transcription factor CEBPε and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1

“…The decommissioning of TF-bound cis-modules after PU.1 induction could be mediated through the reallocation of limiting SWI/SNF remodeling complexes by PU.1, which are generally required to maintain the accessible state of regulatory elements such as lineage-specific enhancers [27][28][29][30] . As many of the identified PU.1 partner proteins have already previously been shown to interact with components of SWI/SNF remodeling complexes [31][32][33][34] , the latter may act as part of a hub increasing the probability of cobinding of PU.1 partner proteins at de novo-remodeled binding sites. In conclusion, our systematic analysis of de novo TF binding reveals important mechanistic details and provides more comprehensive understanding of a master regulator that shapes regulatory landscapes during hematopoiesis, has known reprogramming capabilities, but is different from "classical" pioneer factors.…”

Unwinding chromatin at the right places: how BAF is targeted to specific genomic locations during development

“…In the same C/EBP family, C/EBPβ, which features a complex N terminus transactivation domain, was found to be essential for mediating BAFdependent myeloid gene activation (Kowenz-Leutz and Leutz, 1999). Furthermore, the interaction between C/EBPɛ and BAF was reported to regulate neutrophil granulocyte differentiation, through direct binding to BAF60B (Priam et al, 2017;Witzel et al, 2017).…”

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

“…ATP-dependent chromatin remodelers play an important role in pluripotency and cellular reprogramming (7,8). Recent studies, including ours, have highlighted that specific members in ATP-dependent chromatin remodelers have critical regulatory roles in hematopoiesis and leukemia pathogenesis (9)(10)(11)(12)(13)(14). Nucleosome remodeling and deacetylase (NuRD) is an ATP-dependent chromatin remodeling complex that critically regulates cell fate commitment and transcriptional architecture of murine embryonic stem cells (7).…”