Alternative titles; symbols
HGNC Approved Gene Symbol: PTBP1
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:797,452-812,312 (from NCBI)
Polypyrimidine tract-binding protein (PTB), also known as heterogeneous nuclear ribonucleoprotein type I (hnRNP I), is a 59.6-kD nuclear protein that binds pre-mRNAs in specific regions of the hnRNA-protein complexes sensitive to micrococcal nuclease. The hnRNP I protein shows an unusual pattern of nuclear localization (Ghetti et al., 1992). It has been implicated in pre-mRNA splicing.
Inclusion of cardiac troponin T (TNNT2; 191045) exon 5 in embryonic muscle requires conserved flanking intronic elements (MSEs). Charlet-B et al. (2002) found that ETR3 (CUGBP2; 602538), a member of the CELF family, binds U/G motifs in 2 MSEs and directly activates exon inclusion in vitro. They showed that binding and activation by ETR3 are directly antagonized by PTB. The use of dominant-negative mutants demonstrated that endogenous CELF and PTB activities are required for MSE-dependent activation and repression in muscle and nonmuscle cells, respectively. Combined use of CELF and PTB dominant-negative mutants provided an in vivo demonstration that antagonistic splicing activities exist within the same cells.
Makeyev et al. (2007) showed that the expression of miR124 (see 609327) in mouse neuronal cells induced a switch from general to neuron-specific alternative splicing by directly targeting the mRNA of Ptbp1. They showed that miR124 increased the abundance of neuron-specific Ptbp2 (608449) and Gabbr1 (603540) mRNAs by preventing Ptbp1-dependent exon skipping that leads to nonsense-mediated decay of these mRNAs. Makeyev et al. (2007) further showed that retinoic acid-induced neuronal differentiation in a mouse embryonal carcinoma cell line resulted in the accumulation of miR124, which correlated with decreased Ptbp1 protein levels, increased Ptbp2 levels, and a switch to neuron-specific alternative splicing.
David et al. (2010) showed that 3 heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, PTB, hnRNPA1 (164017), and hnRNPA2 (600124), bind repressively to sequences flanking exon 9 of the PKM2 gene (179050), resulting in exon 10 inclusion and the expression of the PKM2 (embryonic) isoform. David et al. (2010) also demonstrated that the oncogenic transcription factor c-MYC (190080) upregulates transcription of PTB, hnRNPA1, and hnRNPA2, ensuring a high PKM2/PKM1 ratio. Establishing a relevance to cancer, David et al. (2010) showed that human gliomas (137800) overexpress c-Myc, PTB, hnRNPA1, and hnRNPA2 in a manner that correlates with PKM2 expression. David et al. (2010) concluded that their results defined a pathway that regulates an alternative splicing event required for tumor cell proliferation.
Luco et al. (2010) demonstrated a direct role for histone modifications, specifically, trimethylation of H3 at lys36 (H3-K36me3; see 602810), in alternative splicing. The authors found that MRG15 (607303) distribution along the PTB-dependent alternatively spliced genes FGFR2 (176943), TPM2 (190990), TPM1 (191010), and PKM2, but not along the control gene CD44 (107269), mimicked H3-K36me3 distribution. Overexpression of MRG15 was sufficient to force exclusion of the PTB-dependent exons but did not significantly alter the inclusion levels of CD44 exon v6. Additional experiments led Luco et al. (2010) to conclude that the chromatin-binding protein MRG15 is a modulator of PTB-dependent alternative splice site selection. The results of Luco et al. (2010) led them to propose the existence of an adaptor system for the reading of histone marks by the pre-mRNA splicing machinery. The adaptor system consists of histone modifications, a chromatin-binding protein that reads the histone marks, and an interacting splicing regulator. Luco et al. (2010) concluded that for a subset of PTB-dependent genes, the adaptor system consists of H3-K36me3, its binding protein MRG15, and the splicing regulator PTBP1.
Neural stem cells (NSCs) of the embryonic cortical ventricular zone (VZ) and adult ventricular-subventricular zone (V-SVZ) are glial cells that can both self-renew and differentiate to yield intermediate progenitors that divide at least once before producing young migratory neurons. Ramos et al. (2015) found that mouse Ptbp1 was coexpressed with the long noncoding RNA Pnky (616328) in nuclei of V-SVZ NSCs. Mass spectrometric analysis and RNA immunoprecipitation revealed that Pnky interacted directly with Ptbp1. Knockdown of either Ptbp1 or Pnky increased neuronal commitment and cell division in mouse NSCs. In addition, knockdown of Pnky or Ptbp1 caused similar changes in gene expression and gene splicing. Expression of Ntsr2 (605538), Igfbp5 (146734), Scrg1 (603163), and Ppp1r3c (602999) was increased in NSCs with single knockdown of Pnky or Ptbp1, and combined knockdown of Pnky and Ptbp1 did not further enhance their expression. Ramos et al. (2015) proposed that PNKY and PTBP1 interact in the same pathway, possibly in a ribonucleoprotein complex, to regulate gene expression in NSCs as well as neurogenesis.
Liu et al. (2017) used single-cell RNA sequencing to analyze global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes. Analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased induced cardiomyocyte reprogramming efficiency.
Qian et al. (2020) reported 1-step conversion of isolated mouse and human astrocytes to functional neurons via depletion of PTBP1. In mouse brain, Ptbp1-depleted astrocytes were progressively converted to new neurons that innervated into and repopulated endogenous neural circuits. Moreover, Ptbp1-depleted astrocytes from different brain regions were converted to different neuronal subtypes. In a mouse model of Parkinson disease, midbrain astrocytes could be converted to dopaminergic neurons, which provided axons to reconstruct the nigrostriatal circuit, via Ptbp1 depletion. Reinnervation of striatum was accompanied by restoration of dopamine levels and rescue of motor deficits. Transient suppression of Ptbp1 through the use of antisense oligonucleotides also converted astrocytes to neurons and produced a similar reversal of disease phenotype.
Using RT-PCR and genomic sequence analysis, Romanelli et al. (2000) showed that the PTB gene contains 15 exons and spans 13.5 kb.
By fluorescence in situ hybridization, Raimondi et al. (1995) assigned the PTB gene to 14q23-q24.1. Other hnRNP protein genes that had been mapped include A1 (164017) to 12q13.1, A2 (600124) to 7p15, and K (600712) to chromosome 9. Southern blot analysis of human DNA demonstrated that the PTB gene is present in single copy.
Using RT-PCR and genomic sequence analysis, Romanelli et al. (2000) showed that the PTB gene is actually localized on chromosome 19, probably at 19p13.3. A highly homologous processed pseudogene maps to chromosome 14.
Oberstrass et al. (2005) determined the solution structures of the 4 RNA-binding domains (RBDs) of PTB, each bound to a CUCUCU oligonucleotide. Each RNA-binding domain binds RNA with a different binding specificity. RBD3 and RBD4 interact, resulting in an antiparallel orientation of their bound RNAs. Thus, PTB will induce RNA looping when bound to 2 separated pyrimidine tracts within the same RNA. Oberstrass et al. (2005) concluded that their data leads to structural models for how PTB functions as an alternative splicing repressor.
Gueroussov et al. (2015) demonstrated that mammalian-specific skipping of PTBP1 exon 9 alters the splicing regulatory activities of PTBP1 and affects the inclusion levels of numerous exons. During neurogenesis, skipping of exon 9 reduces PTBP1 repressive activity so as to facilitate activation of a brain-specific alternative splicing program. Engineered skipping of the orthologous exon in chicken cells induced a large number of mammalian-like alternative splicing changes in PTBP1 target exons. Gueroussov et al. (2015) concluded that a single exon-skipping event in an RNA binding regulator directs numerous alternative splicing changes between species and suggested that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems.
Charlet-B, N., Logan, P., Singh, G., Cooper, T. A. Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Molec. Cell 9: 649-658, 2002. [PubMed: 11931771] [Full Text: https://doi.org/10.1016/s1097-2765(02)00479-3]
David, C. J., Chen, M., Assanah, M., Canoll, P., Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: 364-368, 2010. [PubMed: 20010808] [Full Text: https://doi.org/10.1038/nature08697]
Ghetti, A., Pinol-Roma, S., Michael, W. M., Morandi, C., Dreyfuss, G. HNRNP I, the polypyrimidine tract-binding protein: distinct nuclear localization and association with hnRNAs. Nucleic Acids Res. 20: 3671-3678, 1992. [PubMed: 1641332] [Full Text: https://doi.org/10.1093/nar/20.14.3671]
Gueroussov, S., Gonatopoulos-Pournatzis, T., Irimia, M., Raj, B., Lin, Z.-Y., Gingras, A.-C., Blencowe, B. J. An alternative splicing event amplifies evolutionary differences between vertebrates. Science 349: 868-872, 2015. [PubMed: 26293963] [Full Text: https://doi.org/10.1126/science.aaa8381]
Liu, Z., Wang, L., Welch, J. D., Ma, H., Zhou, Y., Vaseghi, H. R., Yu, S., Wall, J. B., Alimohamadi, S., Zheng, M., Yin, C., Shen, W., Prins, J. F., Liu, J., Qian, L. Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature 551: 100-104, 2017. [PubMed: 29072293] [Full Text: https://doi.org/10.1038/nature24454]
Luco, R. F., Pan, Q., Tominaga, K., Blencowe, B. J., Pereira-Smith, O. M., Misteli, T. Regulation of alternative splicing by histone modifications. Science 327: 996-1000, 2010. [PubMed: 20133523] [Full Text: https://doi.org/10.1126/science.1184208]
Makeyev, E. V., Zhang, J., Carrasco, M. A., Maniatis, T. The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molec. Cell 27: 435-448, 2007. [PubMed: 17679093] [Full Text: https://doi.org/10.1016/j.molcel.2007.07.015]
Oberstrass, F. C., Auweter, S. D., Erat, M., Hargous, Y., Henning, A., Wenter, P., Reymond, L., Amir-Ahmady, B., Pitsch, S., Black, D. L., Allain, F. H.-T. Structure of PTB bound to RNA: specific binding and implications for splicing regulation. Science 309: 2054-2057, 2005. [PubMed: 16179478] [Full Text: https://doi.org/10.1126/science.1114066]
Qian, H., Kang, X., Hu, J., Zhang, D., Liang, Z., Meng, F., Zhang, X., Xue, Y., Maimon, R., Dowdy, S. F., Devaraj, N. K., Zhou, Z., Mobley, W. C., Cleveland, D. W., Fu, X.-D. Reversing a model of Parkinson's disease with in situ converted nigral neurons. Nature 582: 550-556, 2020. Note: Erratum: Nature 584: E17 only, 2020. [PubMed: 32581380] [Full Text: https://doi.org/10.1038/s41586-020-2388-4]
Raimondi, E., Romanelli, M. G., Moralli, D., Gamberi, C., Russo, M. P., Morandi, C. Assignment of the human gene encoding heterogeneous nuclear RNA ribonucleoprotein I (PTB) to chromosome 14q23-q24.1. Genomics 27: 553-555, 1995. [PubMed: 7558043] [Full Text: https://doi.org/10.1006/geno.1995.1093]
Ramos, A. D., Andersen, R. E., Liu, S. J., Nowakowski, T. J., Hong, S. J., Gertz, C. C., Salinas, R. D., Zarabi, H., Kriegstein, A. R., Lim, D. A. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell 16: 439-447, 2015. [PubMed: 25800779] [Full Text: https://doi.org/10.1016/j.stem.2015.02.007]
Romanelli, M. G., Lorenzi, P., Morandi, C. Organization of the human gene encoding heterogeneous nuclear ribonucleoprotein type I (hnRNP I) and characterization of hnRNP I related pseudogene. Gene 255: 267-272, 2000. [PubMed: 11024286] [Full Text: https://doi.org/10.1016/s0378-1119(00)00331-0]