Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2.
During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. In addition, CRISPR/Cas9-mediated deletion of hnRNPH2 selectively accelerates the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. In sum, HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation.
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Ioannis
I
Grammatikakis
Laboratory of Neurosciences, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Peisu
P
Zhang
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Amaresh C
AC
Panda
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Jiyoung
J
Kim
Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium.
Stuart
S
Maudsley
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Kotb
K
Abdelmohsen
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Xiaoling
X
Yang
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Jennifer L
JL
Martindale
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Omar
O
Motiño
Laboratory of Neurosciences, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Emmette R
ER
Hutchison
Laboratory of Neurosciences, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Mark P
MP
Mattson
Laboratory of Genetics, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA. Electronic address: myriam-gorospe@nih.gov.
Myriam
M
Gorospe
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D005091:Exons / Q000235:genetics; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D040901:Proteomics; D012313:RNA / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics; D051381:Rats; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D012322:RNA Precursors; D035341:Telomeric Repeat Binding Protein 2; D012313:RNA
HNRNPH; TRF2; TRF2-S; alternative splicing; mRNA; ribonucleoprotein complex