The homeodomain of Oct4 is a dimeric binder of methylated CpG elements

Tan，Daisylyn Senna1; Cheung，Shun Lai1; Gao，Ya1; Weinbuch，Maike1,2; Hu，Haoqing1; Shi，Liyang3; Ti，Shih Chieh1; Hutchins，Andrew P.3; Cojocaru，Vlad4,5,6; Jauch，Ralf1,7

2023-02-22

10.1093/nar/gkac1262

Nucleic Acids Research   影响因子和分区

0305-1048

1362-4962

Oct4 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.

SCI

英语

其他

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000910119600001

OXFORD UNIV PRESS

BIOLOGY & BIOCHEMISTRY

2-s2.0-85159704319

Scopus

1.School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong
2.Institute for Molecular Medicine,Ulm University,Ulm,Germany
3.Shenzhen Key Laboratory of Gene Regulation and Systems Biology,Department of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,518055,China
4.STAR-UBB Institute,Babeş-Bolyai University,Cluj-Napoca,Romania
5.Computational Structural Biology Group,Utrecht University,Netherlands
6.Max Planck Institute for Molecular Biomedicine,Münster,Germany
7.Centre for Translational Stem Cell Biology,Hong Kong

Tan，Daisylyn Senna,Cheung，Shun Lai,Gao，Ya,et al. The homeodomain of Oct4 is a dimeric binder of methylated CpG elements[J]. Nucleic Acids Research,2023,51(3):1120-1138.

Tan，Daisylyn Senna.,Cheung，Shun Lai.,Gao，Ya.,Weinbuch，Maike.,Hu，Haoqing.,...&Jauch，Ralf.(2023).The homeodomain of Oct4 is a dimeric binder of methylated CpG elements.Nucleic Acids Research,51(3),1120-1138.

Tan，Daisylyn Senna,et al."The homeodomain of Oct4 is a dimeric binder of methylated CpG elements".Nucleic Acids Research 51.3(2023):1120-1138.