ZBTB12 is a Molecular Barrier to Dedifferentiation in Human Pluripotent Stem Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Feb 9

PMID 36759523

Authors

Dasol Han

Guojing Liu

Yujeong Oh

Seyoun Oh

Seungbok Yang

Lori Mandjikian

Neha Rani

Maria C Almeida

Kenneth S Kosik

Jiwon Jang

Affiliations

Soon will be listed here.

Abstract

Development is generally viewed as one-way traffic of cell state transition from primitive to developmentally advanced states. However, molecular mechanisms that ensure the unidirectional transition of cell fates remain largely unknown. Through exact transcription start site mapping, we report an evolutionarily conserved BTB domain-containing zinc finger protein, ZBTB12, as a molecular barrier for dedifferentiation of human pluripotent stem cells (hPSCs). Single-cell RNA sequencing reveals that ZBTB12 is essential for three germ layer differentiation by blocking hPSC dedifferentiation. Mechanistically, ZBTB12 fine-tunes the expression of human endogenous retrovirus H (HERVH), a primate-specific retrotransposon, and targets specific transcripts that utilize HERVH as a regulatory element. In particular, the downregulation of HERVH-overlapping long non-coding RNAs (lncRNAs) by ZBTB12 is necessary for a successful exit from a pluripotent state and lineage derivation. Overall, we identify ZBTB12 as a molecular barrier that safeguards the unidirectional transition of metastable stem cell fates toward developmentally advanced states.

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References

Kapusta A, Kronenberg Z, Lynch V, Zhuo X, Ramsay L, Bourque G . Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet. 2013; 9(4):e1003470. PMC: 3636048. DOI: 10.1371/journal.pgen.1003470. View

Nelson D, Goodchild N, Mager D . Gain of Sp1 sites and loss of repressor sequences associated with a young, transcriptionally active subset of HERV-H endogenous long terminal repeats. Virology. 1996; 220(1):213-8. DOI: 10.1006/viro.1996.0303. View

Collins T, Stone J, Williams A . All in the family: the BTB/POZ, KRAB, and SCAN domains. Mol Cell Biol. 2001; 21(11):3609-15. PMC: 86980. DOI: 10.1128/MCB.21.11.3609-3615.2001. View

Wang J, Xie G, Singh M, Ghanbarian A, Rasko T, Szvetnik A . Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature. 2014; 516(7531):405-9. DOI: 10.1038/nature13804. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

Percharde M, Lin C, Yin Y, Guan J, Peixoto G, Bulut-Karslioglu A . A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity. Cell. 2018; 174(2):391-405.e19. PMC: 6046266. DOI: 10.1016/j.cell.2018.05.043. View

Kumar S, Stecher G, Li M, Knyaz C, Tamura K . MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. Mol Biol Evol. 2018; 35(6):1547-1549. PMC: 5967553. DOI: 10.1093/molbev/msy096. View

Rostovskaya M, Stirparo G, Smith A . Capacitation of human naïve pluripotent stem cells for multi-lineage differentiation. Development. 2019; 146(7). PMC: 6467473. DOI: 10.1242/dev.172916. View

10.

Wang D, Zhang Y, Zhang Z, Zhu J, Yu J . KaKs_Calculator 2.0: a toolkit incorporating gamma-series methods and sliding window strategies. Genomics Proteomics Bioinformatics. 2010; 8(1):77-80. PMC: 5054116. DOI: 10.1016/S1672-0229(10)60008-3. View

11.

Oshima M, Knoch K, Diedisheim M, Petzold A, Cattan P, Bugliani M . Virus-like infection induces human β cell dedifferentiation. JCI Insight. 2018; 3(3). PMC: 5821176. DOI: 10.1172/jci.insight.97732. View

12.

Lynch C, Bernad R, Martinez-Val A, Shahbazi M, Nobrega-Pereira S, Calvo I . Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases. Nat Cell Biol. 2020; 22(10):1223-1238. DOI: 10.1038/s41556-020-0573-1. View

13.

Niwa H, Ogawa K, Shimosato D, Adachi K . A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009; 460(7251):118-22. DOI: 10.1038/nature08113. View

14.

James D, Levine A, Besser D, Hemmati-Brivanlou A . TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development. 2005; 132(6):1273-82. DOI: 10.1242/dev.01706. View

15.

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

16.

Conaco C, Bassett D, Zhou H, Arcila M, Degnan S, Degnan B . Functionalization of a protosynaptic gene expression network. Proc Natl Acad Sci U S A. 2012; 109 Suppl 1:10612-8. PMC: 3386881. DOI: 10.1073/pnas.1201890109. View

17.

Bourque G, Leong B, Vega V, Chen X, Lee Y, Srinivasan K . Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res. 2008; 18(11):1752-62. PMC: 2577865. DOI: 10.1101/gr.080663.108. View

18.

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

19.

Goke J, Lu X, Chan Y, Ng H, Ly L, Sachs F . Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells. Cell Stem Cell. 2015; 16(2):135-41. DOI: 10.1016/j.stem.2015.01.005. View

20.

Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell. 2009; 4(6):487-92. DOI: 10.1016/j.stem.2009.05.015. View