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Genes Dev. 2018 Sep 1;32(17-18):1161-1174. doi: 10.1101/gad.316984.118. Epub 2018 Aug 16.

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

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Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Child Health Institute of New Jersey, New Brunswick, New Jersey 08901, USA.
The Center for Stem Cell Biology, Sloan Kettering Institute, New York, New York 10065, USA.
Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA.


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.


E2A; T-cell factor 3; alternative splicing; heterogeneous nuclear ribonucleoprotein; human embryonic stem cell

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