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

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

doi:10.1101/gad.316984.118

Cited by 65 publications

(85 citation statements)

References 70 publications

(83 reference statements)

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“…hnRNPF/H are RNA-binding proteins with relatively well-characterized roles in mRNA splicing (Wang et al, 2012; Wang et al, 2007; Yamazaki et al, 2018), and our RNA-Seq analysis of hnRNPF/H KD cells reveal hundreds of altered splicing events (see Supplemental Figures S7B-C for examples), consistent with previous studies (Yamazaki et al, 2018). How do these changes in RNA splicing - or, alternatively, some unrelated activity of hnRNPF/H - ultimately drive repression of the MERVL program?…”

Section: Discussionsupporting

confidence: 90%

“…Double knockdown of hnRNPF/H resulted in dramatic alterations in expression of several hundred genes ( Figure 5A ), including significant downregulation of developmentally-relevant genes ( Sfrp4 , Otx2 , Dact2 , Spry1/4 , Gbx2 , Notum , Notch4 , Sall1, Fgf15 , Tdgf1 , Inhbb , Ltbp3 , Fgf4 , Pou4f2 , Prdm14 , Lefty2 , Bmp4 , etc.). The misregulation of this wide array of differentiation-associated genes presumably results from the recently-discovered role for hnRNPF/H in alternative splicing of Tcf3, a key transcription factor involved in stem cell maintenance and differentiation (Yamazaki et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

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Control of noncoding RNA production and histone levels by a 5′ tRNA fragment

Bošković

Bing

Kaymak

et al. 2018

Preprint

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Small RNAs derived from mature tRNAs, referred to as tRNA fragments or "tRFs", are an emerging class of regulatory RNAs with poorly understood functions in cellular regulation. We recently identified a role for one specific tRF -5' tRF-Gly-GCC, or tRF-GG -in repression of genes associated with the endogenous retroelement MERVL, but the mechanistic basis for this regulation was unknown. Here, we show that tRF-GG plays a role in production of a wide variety of noncoding RNAs normally synthesized in Cajal bodies. Among these noncoding RNAs, tRF-GG regulation of the U7 snRNA modulates heterochromatin-mediated transcriptional repression of MERVL elements by supporting an adequate supply of histone proteins. Importantly, the effects of inhibiting tRF-GG on histone mRNA levels, activity of a histone 3' UTR reporter, and ultimately on MERVL regulation could all be suppressed by the U7 RNA. We show that the related RNA-binding proteins hnRNPF and H bind directly to tRF-GG, and are required for Cajal body biogenesis. Together, our data reveal a conserved mechanism for 5' tRNA fragment control of noncoding RNA biogenesis and, consequently, in global chromatin organization.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Control of noncoding RNA production and histone levels by a 5′ tRNA fragment

Bošković

Bing

Kaymak

et al. 2018

Preprint

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“…For example, hnRNP H1 and hnRNP F control the inclusion of the E12 or E47 exons of TCF3. Interestingly, the inclusion of the exon E47 is associated to cell differentiation, whereas E12 inclusion contributes to the maintenance of pluripotency [42].…”

Section: A Finely Regulated As Network Controls Human Embryonic Stem mentioning

confidence: 99%

An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

Biamonti

Infantino

Gaglio

et al. 2019

Cells

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During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue-and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.

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“…Based on these results, we concluded that recruitment of a robust transcriptional activator to the hTERT promoter in differentiated fibroblasts led to only mild accumulation of telomerase mRNA.We next sought to explore the impact of post-transcriptional processing on the abundance and stability of hTERT mRNA in ESCs. Specifically, we focused on alternative splicing of pre-mRNA as a regulatory pathway that has been previously shown to control developmentallyregulated genes and pluripotency-associated factors (20)(21)(22)(23)(24)(25). Many hTERT alternative splice variants have been detected in different cell types, including α/β variants that modulate telomerase activity in cancer cells (26-28).…”

mentioning

confidence: 99%

Alternative splicing is a developmental switch for hTERT expression

Penev¹,

Bazley²,

Shen

et al. 2020

Preprint

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2 Penev et al.,High telomerase activity is restricted to the blastocyst stage of embryonic development when telomere length is reset, and is characteristic of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, the pathways involved in telomerase regulation as a function of pluripotency remain unknown. To explore hTERT transcriptional control, we compare genome-wide interactions (4C-seq) and chromatin accessibility (ATAC-seq) between human ESCs and epithelial cells and identify several putative hTERT cis-regulatory elements. CRISPR/Cas9-mediated deletion of candidate elements in ESCs reduces the levels of hTERT mRNA but does not abolish telomerase expression, thus implicating post-transcriptional processes in telomerase regulation. In agreement with this hypothesis, we find an hTERT splice variant lacking exon-2 and prone to degradation, to be enriched in differentiated cells but absent from ESCs. In addition, we show that forced retention of exon-2 prevents telomerase silencing during differentiation.Lastly, we highlight a role for the splicing co-factor SON in hTERT exon-2 inclusion and identify a SON mutation in a Dyskeratosis congenita patient with short telomeres and decreased telomerase activity. Altogether, our data uncover a novel alternative splice switch that is critical for telomerase activity during development.Telomerase counteracts telomere erosion and promotes cellular immortality. This specialized ribonucleoprotein complex is minimally composed of a reverse-transcriptase protein subunit (TERT) and an integral telomerase RNA component (TR). While the expression of telomerase RNA is ubiquitous (1, 2), TERT levels are tightly regulated (3). Human TERT (hTERT) is turned on during the blastocyst stage of embryonic development when telomere length is reestablished (4), and subsequently downregulated in most somatic cells (4,5). Similarly, hTERT becomes activated during the process of nuclear reprogramming (6) and is essential for telomere maintenance in pluripotent cells (7). Upregulation of telomerase occurs in approximately 90% of cancers, allowing tumor cells to escape crisis and proliferate indefinitely (5,8). Somatic mutations in the hTERT promoter have been reported in a subset of cancers and shown to increase telomerase activity by creating a binding site for ETS family transcription factors (9-11). To date, the underlying mechanism that activates hTERT during development and its subsequent silencing in somatic tissues remains unknown.The core hTERT promoter contains numerous binding sites for pluripotency and growthrelated transcription factors, including Myc, Klf4, and Sp1, but expression of these different factors 3 Penev et al., is not sufficient for hTERT accumulation and telomerase activation in somatic cells (12). We therefore sought to identify cis-regulatory elements (REs) that could account for the difference in hTERT mRNA levels between pluripotent and somatic cells ( Figure S1A). Active REs are known to directly contact the promoters they regulate and h...

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

Cited by 65 publications

References 70 publications

Control of noncoding RNA production and histone levels by a 5′ tRNA fragment

Control of noncoding RNA production and histone levels by a 5′ tRNA fragment

An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

Alternative splicing is a developmental switch for hTERT expression

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