TCF3 alternative splicing controlled by hnRNP H/F regulates E-cadherin expression and hESC pluripotency

Takashi Yamazaki, Lizhi Liu, Denis Lazarev, Amr Al-Zain, Vitalay Fomin, Percy Luk Yeung, Stuart M. Chambers, Chi Wei Lu, Lorenz Studer, James L. Manley

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Alternative splicing (AS) plays important roles in embryonic stem cell (ESC) differentiation. In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing. We found that hnRNP H/F levels are high in hESCs, leading to high E12 expression, but decrease during differentiation, switching splicing to produce elevated E47 levels. Importantly, hnRNP H/F knockdown not only recapitulated the switch in TCF3 AS but also destabilized hESC colonies and induced differentiation. Providing an explanation for this, we show that expression of known TCF3 target E-cadherin, critical for maintaining ESC pluripotency, is repressed by E47 but not by E12.

Original languageEnglish (US)
Pages (from-to)1161-1174
Number of pages14
JournalGenes and Development
Volume32
Issue number17-18
DOIs
StatePublished - Sep 1 2018

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Alternative splicing
  • E2A
  • Heterogeneous nuclear ribonucleoprotein
  • Human embryonic stem cell
  • T-cell factor 3

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