7xrc
Crystal Structure of the dimeric Brn2 (Pou3f2) POU domain bound to palindromic MORE DNA
Structural highlights
FunctionPO3F2_HUMAN Transcription factor that plays a key role in neuronal differentiation (By similarity). Binds preferentially to the recognition sequence which consists of two distinct half-sites, ('GCAT') and ('TAAT'), separated by a non-conserved spacer region of 0, 2, or 3 nucleotides (By similarity). Acts as a transcriptional activator when binding cooperatively with SOX4, SOX11, or SOX12 to gene promoters (By similarity). The combination of three transcription factors, ASCL1, POU3F2/BRN2 and MYT1L, is sufficient to reprogram fibroblasts and other somatic cells into induced neuronal (iN) cells in vitro (By similarity). Acts downstream of ASCL1, accessing chromatin that has been opened by ASCL1, and promotes transcription of neuronal genes (By similarity).[UniProtKB:P31360][UniProtKB:P56222] Publication Abstract from PubMedOct4 is essential to maintain pluripotency and has a pivotal role in establishing the germline. Its DNA-binding POU domain was recently found to bind motifs with methylated CpG elements normally associated with epigenetic silencing. However, the mode of binding and the consequences of this capability has remained unclear. Here, we show that Oct4 binds to a compact palindromic DNA element with a methylated CpG core (CpGpal) in alternative states of pluripotency and during cellular reprogramming towards induced pluripotent stem cells (iPSCs). During cellular reprogramming, typical Oct4 bound enhancers are uniformly demethylated, with the prominent exception of the CpGpal sites where DNA methylation is often maintained. We demonstrate that Oct4 cooperatively binds the CpGpal element as a homodimer, which contrasts with the ectoderm-expressed POU factor Brn2. Indeed, binding to CpGpal is Oct4-specific as other POU factors expressed in somatic cells avoid this element. Binding assays combined with structural analyses and molecular dynamic simulations show that dimeric Oct4-binding to CpGpal is driven by the POU-homeodomain whilst the POU-specific domain is detached from DNA. Collectively, we report that Oct4 exerts parts of its regulatory function in the context of methylated DNA through a DNA recognition mechanism that solely relies on its homeodomain. The homeodomain of Oct4 is a dimeric binder of methylated CpG elements.,Tan DS, Cheung SL, Gao Y, Weinbuch M, Hu H, Shi L, Ti SC, Hutchins AP, Cojocaru V, Jauch R Nucleic Acids Res. 2023 Feb 22;51(3):1120-1138. doi: 10.1093/nar/gkac1262. PMID:36631980[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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