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SMARCA4

Official Full Name
SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4
Organism
Homo sapiens
GeneID
6597
Background
The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
Synonyms
BRG1; CSS4; SNF2; SWI2; MRD16; RTPS2; BAF190; OTSC12; SNF2L4; SNF2LB; hSNF2b; BAF190A; SNF2-beta;
Bio Chemical Class
Acid anhydride hydrolase
Protein Sequence
MSTPDPPLGGTPRPGPSPGPGPSPGAMLGPSPGPSPGSAHSMMGPSPGPPSAGHPIPTQGPGGYPQDNMHQMHKPMESMHEKGMSDDPRYNQMKGMGMRSGGHAGMGPPPSPMDQHSQGYPSPLGGSEHASSPVPASGPSSGPQMSSGPGGAPLDGADPQALGQQNRGPTPFNQNQLHQLRAQIMAYKMLARGQPLPDHLQMAVQGKRPMPGMQQQMPTLPPPSVSATGPGPGPGPGPGPGPGPAPPNYSRPHGMGGPNMPPPGPSGVPPGMPGQPPGGPPKPWPEGPMANAAAPTSTPQKLIPPQPTGRPSPAPPAVPPAASPVMPPQTQSPGQPAQPAPMVPLHQKQSRITPIQKPRGLDPVEILQEREYRLQARIAHRIQELENLPGSLAGDLRTKATIELKALRLLNFQRQLRQEVVVCMRRDTALETALNAKAYKRSKRQSLREARITEKLEKQQKIEQERKRRQKHQEYLNSILQHAKDFKEYHRSVTGKIQKLTKAVATYHANTEREQKKENERIEKERMRRLMAEDEEGYRKLIDQKKDKRLAYLLQQTDEYVANLTELVRQHKAAQVAKEKKKKKKKKKAENAEGQTPAIGPDGEPLDETSQMSDLPVKVIHVESGKILTGTDAPKAGQLEAWLEMNPGYEVAPRSDSEESGSEEEEEEEEEEQPQAAQPPTLPVEEKKKIPDPDSDDVSEVDARHIIENAKQDVDDEYGVSQALARGLQSYYAVAHAVTERVDKQSALMVNGVLKQYQIKGLEWLVSLYNNNLNGILADEMGLGKTIQTIALITYLMEHKRINGPFLIIVPLSTLSNWAYEFDKWAPSVVKVSYKGSPAARRAFVPQLRSGKFNVLLTTYEYIIKDKHILAKIRWKYMIVDEGHRMKNHHCKLTQVLNTHYVAPRRLLLTGTPLQNKLPELWALLNFLLPTIFKSCSTFEQWFNAPFAMTGEKVDLNEEETILIIRRLHKVLRPFLLRRLKKEVEAQLPEKVEYVIKCDMSALQRVLYRHMQAKGVLLTDGSEKDKKGKGGTKTLMNTIMQLRKICNHPYMFQHIEESFSEHLGFTGGIVQGLDLYRASGKFELLDRILPKLRATNHKVLLFCQMTSLMTIMEDYFAYRGFKYLRLDGTTKAEDRGMLLKTFNEPGSEYFIFLLSTRAGGLGLNLQSADTVIIFDSDWNPHQDLQAQDRAHRIGQQNEVRVLRLCTVNSVEEKILAAAKYKLNVDQKVIQAGMFDQKSSSHERRAFLQAILEHEEQDESRHCSTGSGSASFAHTAPPPAGVNPDLEEPPLKEEDEVPDDETVNQMIARHEEEFDLFMRMDLDRRREEARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKMFGRGSRHRKEVDYSDSLTEKQWLKAIEEGTLEEIEEEVRQKKSSRKRKRDSDAGSSTPTTSTRSRDKDDESKKQKKRGRPPAEKLSPNPPNLTKKMKKIVDAVIKYKDSSSGRQLSEVFIQLPSRKELPEYYELIRKPVDFKKIKERIRNHKYRSLNDLEKDVMLLCQNAQTFNLEGSLIYEDSIVLQSVFTSVRQKIEKEDDSEGEESEEEEEGEEEGSESESRSVKVKIKLGRKEKAQDRLKGGRRRPSRGSRAKPVVSDDDSEEEQEEDRSGSGSEED
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Detailed Information

The SMARCA4 gene (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin, Subfamily A, Member 4) is located on human chromosome 19q13.2 and contains 38 exons. This gene encodes the BRG1 protein, which is composed of 1,870 amino acids and functions as the ATPase catalytic subunit of the SWI/SNF chromatin remodeling complex.

BRG1 Protein Structure and Mechanisms

The BRG1 protein belongs to the SF2 superfamily of DNA-dependent ATPases. Its conserved enzymatic center hydrolyzes ATP to provide energy for remodeling nucleosome–DNA interactions, thereby regulating chromatin accessibility. Structurally, BRG1 contains several key domains:

  • The HSA domain at the N-terminus mediates interactions with actin-associated proteins.
  • The central ATPase domain, which generates chemical energy for chromatin remodeling.
  • The C-terminal bromodomain, which specifically recognizes acetylated histone residues such as H3K14ac, anchors the remodeling complex to particular genomic regions.

This multi-domain organization makes BRG1 the molecular engine of SWI/SNF chromatin remodeling activity.

Figure 1. Schematic diagram of the molecular and DNA association of BRG1 with targets related to cardiac hypertrophy.Figure 1. Schematic diagram of the molecular and DNA association of BRG1 with targets related to cardiac hypertrophy. (Ma ZY, et al., 2023)

Nuclear Functions of BRG1

Within the nucleus, BRG1 catalyzes chromatin remodeling through three main mechanisms:

  1. Nucleosome sliding to expose transcription factor binding sites.
  2. Nucleosome eviction from selected DNA regions to create open chromatin.
  3. Nucleosome exchange, adjusting accessibility of regulatory elements.

These actions directly influence the recruitment of transcriptional activators, repressors, and RNA polymerase II to promoters and enhancers, enabling precise transcriptional control. Importantly, BRG1 functions in a developmentally and tissue-specific manner. For example, during neurodevelopment, BRG1-containing npBAF complexes maintain neural progenitor proliferation, while differentiation into neurons requires replacement by nBAF complexes, a process tightly regulated by non-coding RNAs such as Evf2.

Physiological Roles of BRG1

BRG1 plays essential roles in embryonic development, lineage differentiation, and metabolic regulation. In mouse models, complete gene deletion leads to embryonic lethality, highlighting its indispensable developmental function. In the nervous system, BRG1 balances self-renewal and differentiation of neural progenitors to ensure cortical development. In brown adipose tissue, BRG1 regulates thermogenic gene expression such as UCP1, contributing to energy metabolism and thermoregulation. It also modulates epithelial–mesenchymal transition (EMT) by cooperating with transcriptional repressors like ZEB1, thereby influencing tissue repair and regeneration.

Pathological Associations

Loss-of-function mutations in SMARCA4 disrupt chromatin remodeling and lead to profound transcriptional dysregulation. In 2021, the WHO classified SMARCA4-deficient undifferentiated tumors as a distinct thoracic tumor entity. These tumors frequently occur in male smokers and are characterized by the complete absence of BRG1 protein expression, often in conjunction with mutations in TP53, KRAS, or STK11. Genomic studies report mutation frequencies of 5–10% in lung cancer overall, with particularly high rates in large cell carcinoma (LCC).

Clinically, SMARCA4-deficient tumors are highly aggressive, with rapid progression and poor response to standard chemotherapy, targeted therapy, and immunotherapy. Unlike other lung cancers, they often lack expression of markers such as TTF1 and p40, and they rarely harbor common actionable driver mutations (e.g., EGFR, ALK, ROS1).

Beyond thoracic malignancies, SMARCA4 deficiency is strongly linked to ovarian hypercalcemic small cell carcinoma (SCCOHT), a rare but aggressive tumor type in young women. In the majority of SCCOHT cases, BRG1 protein expression is absent, which makes SMARCA4 immunohistochemistry an important diagnostic tool to distinguish SCCOHT from morphologically similar ovarian tumors.

Clinical Significance

In pathology practice, SMARCA4 immunohistochemistry is now widely applied for diagnosing poorly differentiated or marker-negative tumors. Two categories of mutations have been described:

  • Class I mutations (nonsense, frameshift, splice site), leading to complete protein loss.
  • Class II mutations (missense), which may retain partial protein function, complicating immunohistochemical interpretation.

In cases with uncertain IHC results, next-generation sequencing (NGS) provides critical confirmation.

Prognostic and Therapeutic Implications

SMARCA4 deficiency is recognized as an independent marker of poor prognosis in lung cancer and other malignancies. The aggressive biology is thought to stem from the combination of high tumor mutation burden and an immunosuppressive microenvironment, limiting responses to immune checkpoint blockade.

Since BRG1 is a tumor suppressor rather than an oncogenic driver, conventional targeted approaches are not feasible. Research is focusing on synthetic lethality strategies:

  • EZH2 inhibitors (e.g., GSK126) exploit functional antagonism between SWI/SNF and PRC2 complexes.
  • CDK4/6 inhibitors and mTOR inhibitors are being investigated in combination approaches.
  • Epigenetic therapies, such as HDAC inhibitors and demethylating agents, are under evaluation.

Although BRG1-deficient tumors usually show low PD-L1 expression, their high mutation burden suggests that some patients may still benefit from immune checkpoint blockade, particularly when combined with treatments that enhance immunogenicity, such as radiotherapy. Clinical trials are ongoing to explore optimal therapeutic strategies based on SMARCA4 status.

Translational Prospects

The study of SMARCA4/BRG1 continues to provide insights into chromatin biology and tumorigenesis. In diagnostics, protein-level detection remains a key tool for classification of aggressive tumor subtypes. In therapeutics, synthetic lethality and epigenetic targeting represent promising approaches for tumors lacking SMARCA4 function. Ultimately, a deeper structural and mechanistic understanding of BRG1 may open avenues for rational drug development and precision oncology.

Reference

  1. Nambirajan A, Singh V, Bhardwaj N, et al. SMARCA4/BRG1-Deficient Non-Small Cell Lung Carcinomas: A Case Series and Review of the Literature. Arch Pathol Lab Med. 2021 Jan 1;145(1):90-98.

  2. Ma ZY, Li J, Dong XH, et al. The role of BRG1 in epigenetic regulation of cardiovascular diseases. Eur J Pharmacol. 2023 Oct 15;957:176039.

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