Brg1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for myeloid differentiation to granulocytes

Abstract

Many mammalian SWI/SNF complexes use Brahma-related gene 1 (Brg1) as a catalytic subunit to remodel nucleosomes for transcription regulation. In several mesenchymal cells and tissues, expression of a defective Brg1 protein negates the normal activity of the SWI/SNF complex and delays or blocks differentiation. To investigate the role of SWI/SNF complexes during myelopoiesis, we stably expressed a dominant negative (dn) Brg1 mutant in the myeloid lineage. Forced expression of dnBrg1 in IL-3-dependent murine 32Dcl3 myeloid progenitor cells results in a profound delay in the granulocyte-colony stimulating factor (G-CSF) induced granulocytic maturation. These cells also exhibit a significant decrease in the expression of both CD11b and Gr-1 surface receptors, which are normally upregulated during granulopoiesis, and show sustained expression of myeloperoxidase, which is synthesized primarily during the promyelocytic (blast) stage of myeloid development. Thus, dnBrg1 expression causes a developmental block at the promyelocytic/metamyelocytic stage of myeloid differentiation. Our findings indicate that the normal chromatin remodeling function of Brg1 is necessary for the G-CSF dependent differentiation of myeloid cells towards the granulocytic lineage. This dependency on Brg1 may reflect a stringent requirement for chromatin remodeling at a critical stage of hematopoietic cell maturation.

Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity

“…Additional roles for Geminin have been reported, such as its repression of transcription by interaction with PcG complex 1, Hox (17), Six3 (31), SMRT, and AP4 (32). It has also been proposed that Geminin maintains undifferentiated cell states by antagonizing activity of Brg1, a subunit of SWI/SNF, which is reportedly crucial for neural and myeloid differentiation from stem and progenitor cells (19,33). This suggests the possible existence of an additional function, namely, that an increase in Geminin further affects cellular differentiation capacity through direct interaction with these factors.…”

Differential gene expression in ACTH -secreting and non-functioning pituitary tumors

“…Brg1, an ATPase subunit of the SWI/SNF chromatin remodeling complex (35), by interacting with GR allows chromatin remodeling (36). It has been reported that HDAC2 and Brg1 are important for glucocorticoid-induced transrepression of the POMC gene in the negative feedback regulation mechanism, and that immunoreactivities of either HDAC2 or Brg1 were deficient in 17 out of 36 (48%) ACTH-secreting pituitary tumors (37).…”

The SWI/SNF complex and cancer

“…RNAimediated knockdown of BAF60 in embryonic stem cells inhibits cardiovascular morphogenesis (Lickert et al, 2004). A dominant-negative BRG1 allele blocks myeloid differentiation of 32Dcl3 cells (Vradii et al, 2006), whereas loss of BRG1 in keratinocytes results in defects in limb patterning (Indra et al, 2005). Studies in embryonic stem cells have revealed that lack of BAF250 can compromise cell pluripotency and severely inhibit self-renewal, whereas functional BAF250 contributes to the proper expression of numerous genes involved in embryonic stem cell self-renewal, including Sox2, Utf1 and Oct4 (Yan et al, 2008) (Gao et al, 2008).…”