Disease relevance of Smarca4

• The mutant Brg1 protein is stable, assembles into SWI/SNF-related complexes, and exhibits normal ATPase activity but is unable to establish DNase I hypersensitivity sites characteristic of open chromatin [1].
• Both Brg1 and Brm are mutated or deleted in numerous cancer cell lines, leading to the altered expression of genes that influence cell proliferation and metastasis [2].

High impact information on Smarca4

• To test this hypothesis, we generated a maternal-effect mutation of Brg1, which encodes a catalytic subunit of SWI/SNF-related complexes, utilizing Cre-loxP gene targeting [3].
• The mutant Brg1 protein is recruited to the beta-globin locus, but chromatin remodeling and transcription are perturbed [1].
• A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development [1].
• The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in many developmental and physiological processes, but null homozygotes die as blastocysts prior to implantation [1].
• Not only does this mutation establish a role for Brg1 during organogenesis, it also demonstrates that ATPase activity can be uncoupled from chromatin remodeling [1].

Biological context of Smarca4

• Mammalian SWI/SNF complexes utilize either brahma (Brm) or brahma-related gene 1 (Brg1) catalytic subunits to remodel nucleosomes in an ATP-dependent manner [4].
• However, experiments with other cell types demonstrate that Brg1 is not a general cell survival factor [4].
• To test this hypothesis, we have generated a Brg1 null mutation by gene targeting, and, surprisingly, homozygotes die during the periimplantation stage [4].
• In addition, Brg1 heterozygotes are predisposed to exencephaly and tumors [4].
• Within this complex, the BRM (SNF2alpha) and BRG1 (SNF2beta) proteins are mutually exclusive subunits that are believed to affect nucleosomal structures using the energy of ATP hydrolysis [5].

Anatomical context of Smarca4

• To further investigate the in vivo role of BRG1, we selectively ablated Brg1 in keratinocytes of the forming mouse epidermis [6].
• By contrast, as Brg1-null fibroblasts are viable but Brg1-null embryos die during the peri-implantation stage, BRG1 might exert cell-specific functions [6].
• In addition, Brg1 is expressed in cells within the developing skeleton of the mouse embryo as well as in osteoblasts ex vivo [7].
• Recent biochemical data has linked Brg1 function to genes important for T lymphocyte differentiation [8].
• However, the Sox2-positive, proliferating neural progenitor cell population was expanded, and expression of a terminally differentiated neuronal marker, N-tubulin, was diminished upon loss of Brg1 activity, suggesting that Brg1 is required for neuronal differentiation [9].

Associations of Smarca4 with chemical compounds

• We show that F9 EC cells inactivated on both SNF2beta alleles are not viable and that heterozygous mutant cells are affected in proliferation but not in RA-induced differentiation [10].
• The DEX-activated promoter possessed similar composition as the basal promoter, but also contains stably bound Brg1 [11].

Physical interactions of Smarca4

• Mammalian SWI-SNF-related complexes use brahma-related gene 1 (Brg1) as a catalytic subunit to remodel nucleosomes and regulate transcription [8].

Regulatory relationships of Smarca4

• Consistent with this, dominant-negative interference with Brg1 function in P19 cells suppressed neuronal differentiation promoted by NeuroD2, showing the requirement of Brg1 for neuronal differentiation is conserved in mammalian cells [9].

Other interactions of Smarca4

• T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-gamma promoter are Stat4 dependent [12].
• We further demonstrated that ectopic expression of myogenin and Mef2D, in the absence of MyoD, was sufficient to induce muscle differentiation in a manner entirely dependent on Brg1 [13].
• The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD [9].
• 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 [14].
• To circumvent this early embryonic lethality, we performed an ENU mutagenesis screen and generated a Brg1 hypomorph mutation in the ATPase domain [1].

References