Epigenetic and Transcriptional Regulations Prime Cell Fate Before Division During Human Pluripotent Stem Cell Differentiation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jan 25

PMID 36697417

Authors

Pedro Madrigal

Siwei Deng

Yuliang Feng

Stefania Militi

Kim Jee Goh

Reshma Nibhani

Rodrigo Grandy

Anna Osnato

Daniel Ortmann

Stephanie Brown

Siim Pauklin

Affiliations

Soon will be listed here.

Abstract

Stem cells undergo cellular division during their differentiation to produce daughter cells with a new cellular identity. However, the epigenetic events and molecular mechanisms occurring between consecutive cell divisions have been insufficiently studied due to technical limitations. Here, using the FUCCI reporter we developed a cell-cycle synchronised human pluripotent stem cell (hPSC) differentiation system for uncovering epigenome and transcriptome dynamics during the first two divisions leading to definitive endoderm. We observed that transcription of key differentiation markers occurs before cell division, while chromatin accessibility analyses revealed the early inhibition of alternative cell fates. We found that Activator protein-1 members controlled by p38/MAPK signalling are necessary for inducing endoderm while blocking cell fate shifting toward mesoderm, and that enhancers are rapidly established and decommissioned between different cell divisions. Our study has practical biomedical utility for producing hPSC-derived patient-specific cell types since p38/MAPK induction increased the differentiation efficiency of insulin-producing pancreatic beta-cells.

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References

Brons I, Smithers L, Trotter M, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes S . Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. 2007; 448(7150):191-5. DOI: 10.1038/nature05950. View

Vallier L, Touboul T, Brown S, Cho C, Bilican B, Alexander M . Signaling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells. Stem Cells. 2009; 27(11):2655-66. DOI: 10.1002/stem.199. View

Falcon S, Gentleman R . Using GOstats to test gene lists for GO term association. Bioinformatics. 2006; 23(2):257-8. DOI: 10.1093/bioinformatics/btl567. View

Li Q, Dixon G, Verma N, Rosen B, Gordillo M, Luo R . Genome-scale screens identify JNK-JUN signaling as a barrier for pluripotency exit and endoderm differentiation. Nat Genet. 2019; 51(6):999-1010. PMC: 6545159. DOI: 10.1038/s41588-019-0408-9. View

. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489(7414):57-74. PMC: 3439153. DOI: 10.1038/nature11247. View

Calder A, Roth-Albin I, Bhatia S, Pilquil C, Lee J, Bhatia M . Lengthened G1 phase indicates differentiation status in human embryonic stem cells. Stem Cells Dev. 2012; 22(2):279-95. DOI: 10.1089/scd.2012.0168. View

Dixon J, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget J, Lee A . Chromatin architecture reorganization during stem cell differentiation. Nature. 2015; 518(7539):331-6. PMC: 4515363. DOI: 10.1038/nature14222. View

Gonzales K, Liang H, Lim Y, Chan Y, Yeo J, Tan C . Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways. Cell. 2015; 162(3):564-79. DOI: 10.1016/j.cell.2015.07.001. View

Sung M, Guertin M, Baek S, Hager G . DNase footprint signatures are dictated by factor dynamics and DNA sequence. Mol Cell. 2014; 56(2):275-285. PMC: 4272573. DOI: 10.1016/j.molcel.2014.08.016. View

10.

Neph S, Vierstra J, Stergachis A, Reynolds A, Haugen E, Vernot B . An expansive human regulatory lexicon encoded in transcription factor footprints. Nature. 2012; 489(7414):83-90. PMC: 3736582. DOI: 10.1038/nature11212. View

11.

Shen L, Shao N, Liu X, Maze I, Feng J, Nestler E . diffReps: detecting differential chromatin modification sites from ChIP-seq data with biological replicates. PLoS One. 2013; 8(6):e65598. PMC: 3677880. DOI: 10.1371/journal.pone.0065598. View

12.

Parker S, Stitzel M, Taylor D, Orozco J, Erdos M, Akiyama J . Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A. 2013; 110(44):17921-6. PMC: 3816444. DOI: 10.1073/pnas.1317023110. View

13.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

14.

Mateos J, Madrigal P, Tsuda K, Rawat V, Richter R, Romera-Branchat M . Combinatorial activities of SHORT VEGETATIVE PHASE and FLOWERING LOCUS C define distinct modes of flowering regulation in Arabidopsis. Genome Biol. 2015; 16:31. PMC: 4378019. DOI: 10.1186/s13059-015-0597-1. View

15.

Chavez A, Scheiman J, Vora S, Pruitt B, Tuttle M, Iyer E . Highly efficient Cas9-mediated transcriptional programming. Nat Methods. 2015; 12(4):326-8. PMC: 4393883. DOI: 10.1038/nmeth.3312. View

16.

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

17.

Chetty S, Engquist E, Mehanna E, Lui K, Tsankov A, Melton D . A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation. J Cell Biol. 2015; 210(7):1257-68. PMC: 4586752. DOI: 10.1083/jcb.201502035. View

18.

Malaguti M, Portero Migueles R, Blin G, Lin C, Lowell S . Id1 Stabilizes Epiblast Identity by Sensing Delays in Nodal Activation and Adjusting the Timing of Differentiation. Dev Cell. 2019; 50(4):462-477.e5. PMC: 6706657. DOI: 10.1016/j.devcel.2019.05.032. View

19.

Chetty S, Pagliuca F, Honore C, Kweudjeu A, Rezania A, Melton D . A simple tool to improve pluripotent stem cell differentiation. Nat Methods. 2013; 10(6):553-6. PMC: 3694177. DOI: 10.1038/nmeth.2442. View

20.

Yiangou L, Grandy R, Morell C, Tomaz R, Osnato A, Kadiwala J . Method to Synchronize Cell Cycle of Human Pluripotent Stem Cells without Affecting Their Fundamental Characteristics. Stem Cell Reports. 2019; 12(1):165-179. PMC: 6335580. DOI: 10.1016/j.stemcr.2018.11.020. View