The SWI/SNF ATP-dependent chromatin remodeling complex in cell lineage priming and early development

Abstract

ATP dependent chromatin remodelers have pivotal roles in transcription, DNA replication and repair, and maintaining genome integrity. SWI/SNF remodelers were first discovered in yeast genetic screens for factors involved in mating type switching or for using alternative energy sources therefore termed SWI/SNF complex (short for SWItch/Sucrose NonFermentable). The SWI/SNF complexes utilize energy from ATP hydrolysis to disrupt histone-DNA interactions and shift, eject, or reposition nucleosomes making the underlying DNA more accessible to specific transcription factors and other regulatory proteins. In development, SWI/SNF orchestrates the precise activation and repression of genes at different stages, safe guards the formation of specific cell lineages and tissues. Dysregulation of SWI/SNF have been implicated in diseases such as cancer, where they can drive uncontrolled cell proliferation and tumor metastasis. Additionally, SWI/SNF defects are associated with neurodevelopmental disorders, leading to disruption of neural development and function. This review offers insights into recent developments regarding the roles of the SWI/SNF complex in pluripotency and cell lineage primining and the approaches that have helped delineate its importance. Understanding these molecular mechanisms is crucial for unraveling the intricate processes governing embryonic stem cell biology and developmental transitions and may potentially apply to human diseases linked to mutations in the SWI/SNF complex.

Keywords: AT-hook; BAF; SWI/SNF; cell fate determination; embryonic stem cells; pluripotency.

Figure 1.. Key changes in major signaling pathways during naïve to primed stage transition.

(A) Key changes in pathways in naïve to primed transition stage. Deletion/mutation of Brg1 AT-hook blocks these signaling pathways and affects cell lineage priming. (B) List of active metabolic genes/pathways in naïve pluripotent stage which are shoutdown in the primed stage. (Atp5pf = ATP synthase-coupling factor 6; Etfdh = electron transfer flavoprotein-ubiquinone oxidoreductase; Acads = short-chain specific acyl-CoA dehydrogenase; G6pc3 = glucose-6-phosphatase 3; Tigar = fructose-2,6-bisphosphatase; Sirt2 = NAD-dependent protein deacetylase sirtuin-2; Gnas = guanine nucleotide-binding protein G(s) subunit α isoform; Gng13 = guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit γ-13; Gpr19 = G-protein coupled receptor 19; Adcy4 = adenylate cyclase type 4; Cyb5r4 = cytochrome b5 reductase 4; 2C44 or Cyp2c23 = cytochrome P450; Acox = peroxisomal acyl-coenzyme A oxidase 1; Ephx2 = bifunctional epoxide hydrolase 2; Phyh = phytanoyl-CoA dioxygenase, peroxisomal; Cdc5L = cell division cycle 5-like protein; Cdc7 = cell division cycle 7-related protein kinase; Asct2 = alanine, serine, cysteine transporter; Ak9 = protein adenylate kinase 9).

Figure 2.. The AT-hook of BRG1 is evolutionarily conserved and targeted in various cancers and neurodevelopmental diseases.

(A) Domain organization of the human SWI/SNF catalytic subunit, BRG1 shown including AT-hook motif at the C-terminus. Number across the top of the schematic represents amino acid positions. (B) Amino acid sequence alignment shown for the AT-hook motifs in human BRG1 and its homologs in Mus musculus (mouse), Gorilla gorilla gorilla (GORGO), Rattus norvegicus (RAT), Gallus gallus (CHICK), Xenopus laevis (XENLA), Danio rerio (DANRE), Saccharomyces cerevisiae (YEAST). Conserved residues are highlighted in yellow and blue. Red arrows indicate amino acids mutated in one or multiple cancer types reported in cBioPortal and blue arrows indicate amino acids mutated in neurodevelopmental diseases as reported in SPARK, DECIPHER, ClinVar [168].