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TCF3 mutually exclusive alternative splicing is controlled by long-range cooperative actions between hnRNPH1 and PTBP1.
RNA. 2019 11; 25(11):1497-1508.RNA

Abstract

TCF3, also known as E2A, is a well-studied transcription factor that plays an important role in stem cell maintenance and hematopoietic development. The TCF3 gene encodes two related proteins, E12 and E47, which arise from mutually exclusive alternative splicing (MEAS). Since these two proteins have different DNA binding and dimerization domains, this AS event must be strictly regulated to ensure proper isoform ratios. Previously, we found that heterogeneous nuclear ribonucleoprotein (hnRNP) H1/F regulates TCF3 AS by binding to exonic splicing silencers (ESSs) in exon 18b. Here, we identify conserved intronic splicing silencers (ISSs) located between, and far from, the two mutually exclusive exons, and show that they are essential for MEAS. Further, we demonstrate that the hnRNP PTBP1 binds the ISS and is a regulator of TCF3 AS. We also demonstrate that hnRNP H1 and PTBP1 regulate TCF3 AS reciprocally, and that position-dependent interactions between these factors are essential for proper TCF3 MEAS. Our study provides a new model in which MEAS is regulated by cooperative actions of distinct hnRNPs bound to ISSs and ESSs.

Authors+Show Affiliations

Department of Biological Sciences, Columbia University, New York, New York 10027, USA.Department of Biological Sciences, Columbia University, New York, New York 10027, USA.Department of Biological Sciences, Columbia University, New York, New York 10027, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

31391218

Citation

Yamazaki, Takashi, et al. "TCF3 Mutually Exclusive Alternative Splicing Is Controlled By Long-range Cooperative Actions Between hnRNPH1 and PTBP1." RNA (New York, N.Y.), vol. 25, no. 11, 2019, pp. 1497-1508.
Yamazaki T, Liu L, Manley JL. TCF3 mutually exclusive alternative splicing is controlled by long-range cooperative actions between hnRNPH1 and PTBP1. RNA. 2019;25(11):1497-1508.
Yamazaki, T., Liu, L., & Manley, J. L. (2019). TCF3 mutually exclusive alternative splicing is controlled by long-range cooperative actions between hnRNPH1 and PTBP1. RNA (New York, N.Y.), 25(11), 1497-1508. https://doi.org/10.1261/rna.072298.119
Yamazaki T, Liu L, Manley JL. TCF3 Mutually Exclusive Alternative Splicing Is Controlled By Long-range Cooperative Actions Between hnRNPH1 and PTBP1. RNA. 2019;25(11):1497-1508. PubMed PMID: 31391218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TCF3 mutually exclusive alternative splicing is controlled by long-range cooperative actions between hnRNPH1 and PTBP1. AU - Yamazaki,Takashi, AU - Liu,Lizhi, AU - Manley,James L, Y1 - 2019/08/07/ PY - 2019/06/12/received PY - 2019/07/31/accepted PY - 2020/11/01/pmc-release PY - 2019/8/9/pubmed PY - 2020/1/7/medline PY - 2019/8/9/entrez KW - PTBP1 KW - TCF3 KW - alternative splicing KW - hnRNPH KW - intronic splicing silencer SP - 1497 EP - 1508 JF - RNA (New York, N.Y.) JO - RNA VL - 25 IS - 11 N2 - TCF3, also known as E2A, is a well-studied transcription factor that plays an important role in stem cell maintenance and hematopoietic development. The TCF3 gene encodes two related proteins, E12 and E47, which arise from mutually exclusive alternative splicing (MEAS). Since these two proteins have different DNA binding and dimerization domains, this AS event must be strictly regulated to ensure proper isoform ratios. Previously, we found that heterogeneous nuclear ribonucleoprotein (hnRNP) H1/F regulates TCF3 AS by binding to exonic splicing silencers (ESSs) in exon 18b. Here, we identify conserved intronic splicing silencers (ISSs) located between, and far from, the two mutually exclusive exons, and show that they are essential for MEAS. Further, we demonstrate that the hnRNP PTBP1 binds the ISS and is a regulator of TCF3 AS. We also demonstrate that hnRNP H1 and PTBP1 regulate TCF3 AS reciprocally, and that position-dependent interactions between these factors are essential for proper TCF3 MEAS. Our study provides a new model in which MEAS is regulated by cooperative actions of distinct hnRNPs bound to ISSs and ESSs. SN - 1469-9001 UR - https://www.unboundmedicine.com/medline/citation/31391218/TCF3_Mutually_Exclusive_Alternative_Splicing_Is_Controlled_by_Long_Range_Cooperative_Actions_between_hnRNPH1_and_PTBP1 DB - PRIME DP - Unbound Medicine ER -