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Hu Proteins Regulate Alternative Splicing by Inducing Localized Hu proteins regulate alternative splicing by PNAS PLUS inducing localized histone hyperacetylation in an RNA-dependent manner Hua-Lin Zhoua, Melissa N. Hinmana, Victoria A. Barrona, Cuiyu Genga, Guangjin Zhoua, Guangbin Luoa,b, Ruth E. Siegelc, and Hua Loua,b,d,1 aDepartment of Genetics, bCase Comprehensive Cancer Center, cDepartment of Pharmacology, dCenter for RNA Molecular Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 Edited by Joan A. Steitz, Howard Hughes Medical Institute, New Haven, CT, and approved July 5, 2011 (received for review March 1, 2011) Recent studies have provided strong evidence for a regulatory link protein CHD1 (18). Moreover, the histone mark H3K36me3 among chromatin structure, histone modification, and splicing reg- can affect alternative splicing by recruiting the splicing regu- ulation. However, it is largely unknown how local histone modifi- lator PTB to pre-mRNA via the chromatin-binding protein cation patterns surrounding alternative exons are connected to MRG15 (19). differential alternative splicing outcomes. Here we show that spli- Chromatin structure regulates various aspects of transcription cing regulator Hu proteins can induce local histone hyperacetyla- that are mediated by RNA polymerase II (RNAPII). As an ob- tion by association with their target sequences on the pre-mRNA vious link between chromatin structure and pre-mRNA splicing, surrounding alternative exons of two different genes. In both the transcriptional behaviors of RNAPII, such as pausing and primary and mouse embryonic stem cell-derived neurons, histone transcriptional elongation rate, have been demonstrated to influ- hyperacetylation leads to an increased local transcriptional elonga- ence alternative splicing outcomes (9, 20–22). To understand how tion rate and decreased inclusion of these exons. Furthermore, we the local rate of transcriptional elongation is regulated to impact demonstrate that Hu proteins interact with histone deacetylase 2 alternative splicing outcomes, it is imperative to investigate the and inhibit its deacetylation activity. We propose that splicing reg- mechanisms by which local chromatin structure and histone mod- BIOCHEMISTRY ulators may actively modulate chromatin structure when recruited ification are modulated. To date, very few studies have addressed to their target RNA sequences cotranscriptionally. This “reaching this question. Given the fact that splicing of pre-mRNA occurs back” interaction with chromatin provides a means to ensure accu- in situ at its chromosomal gene location, it is expected that rate and efficient regulation of alternative splicing. cross-talk can occur in both directions (10). In this context, it is reasonable to propose that splicing regulators, in most cases histone acetylation ∣ neurofibromatosis type 1 ∣ Fas RNA-binding proteins, modulate histone modifications in a loca- lized and RNA-dependent manner. However, to date, no exam- ecent genome-wide transcriptome analysis has demonstrated ples have been discovered to suggest an active role for splicing Rthat more than 95% of human genes undergo alternative spli- regulators in modulating chromatin structure, transcriptional cing to produce multiple proteins from one gene (1–4). Most of elongation rate, and alternative splicing. these alternative splicing events lead to coding differences and Here we describe experiments that reveal a unique functional occur in a cell type- and/or developmental stage-specific manner connection between the roles of Hu RNA-binding proteins in (3, 5), underscoring the essential role of alternative splicing in regulating alternative splicing and histone acetylation. The Hu gene expression control. In addition to the well-established role proteins (HuA/R, HuB, HuC, and HuD) are a family of mamma- of RNA-binding proteins in the regulation of pre-mRNA alter- lian RNA-binding proteins. Of the four Hu family members, native splicing (6, 7), recent studies have revealed a role for chro- HuA/R is widely expressed in many cell types, whereas HuB, matin-associated proteins and the transcription machinery in HuC, and HuD, are expressed specifically in neurons. We have – splicing regulation (8 10). previously demonstrated a role for Hu proteins as splicing regu- A recent study of large human genes demonstrated that pre- lators (23). To date, at least four splicing targets of Hu proteins – mRNA splicing is cotranscriptional and occurs within 5 10 min of have been identified (23–27). These studies show that Hu pro- synthesis (11). The tight coupling of transcription and splicing teins bind to uridine (U)-rich or adenosine/uridine (AU)-rich predicts cross-talk between chromatin structure and splicing RNA sequences and interact with spliceosomal factors to regu- regulation. Indeed, several recent studies have documented a late exon inclusion negatively or positively. number of interesting links between chromatin features and We report a unique mechanism by which Hu proteins increase exon behavior. First, a ChIP analysis indicated that a specific histone acetylation in regions surrounding alternative exons histone modification, trimethylation of lysine 36 of histone H3 leading to an increased local elongation rate and decreased inclu- (H3K36me3), differentially marks exons (12, 13). Remarkably, sion of these exons. Importantly, this regulation occurs through this histone mark appears to be associated more significantly with the association of Hu proteins with their target sequences on constitutive exons than with alternative exons (13). Second, a genome-wide analysis of nucleosome occupancy showed that nu- cleosomes are enriched in exons and are depleted in introns, Author contributions: H.-L.Z. and H.L. designed research; H.-L.Z., M.N.H., V.A.B., and C.G. suggesting that nucleosome position helps to distinguish introns performed research; H.-L.Z., G.Z., G.L., and R.E.S. contributed new reagents/analytic tools; from exons (12, 14–17). Although these studies provide signifi- H.-L.Z. analyzed data; and H.-L.Z. and H.L. wrote the paper. cant evidence for cross-talk between chromatin and splicing, the The authors declare no conflict of interest. nature of the cross-talk remains largely unknown. Several studies This article is a PNAS Direct Submission. support a model in which histone marks function to recruit basal Freely available online through the PNAS open access option. spliceosomal factors or splicing regulators to ensure efficient 1To whom correspondence should be addressed. E-mail: [email protected]. splicing regulation. For example, the histone mark H3K4me3 See Author Summary on page 14717. was shown to facilitate efficient splicing through recruiting the This article contains supporting information online at www.pnas.org/lookup/suppl/ spliceosomal component U2 snRNP via the H3K4me3 binding doi:10.1073/pnas.1103344108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1103344108 PNAS ∣ September 6, 2011 ∣ vol. 108 ∣ no. 36 ∣ E627–E635 Downloaded by guest on October 7, 2021 nascent pre-mRNA molecules. Furthermore, we show that Hu A proteins decrease the deacetylation activity of histone deacetylase Neuron: 23 24 NF1 23 23a 2 (HDAC2). We propose that splicing regulators may actively 24 ES: 23 23a 24 modulate chromatin structure when recruited to their target Neuron: 5 7 RNA sequences cotranscriptionally. This “reaching back” inter- Fas 5 6 7 action with chromatin provides a means to ensure accurate and ES: 5 6 7 efficient regulation of alternative splicing, supporting a more dynamic and integrated view of gene expression control. B C Results Hu Proteins Associate with Transcriptionally Active RNAPII in Neuronal Cells. Our previous studies demonstrated that Hu proteins play an 23 23a 24 5 6 7 important role in the nucleus as alternative splicing regulators. As splicing occurs in situ at the site of transcription (11), we exam- 23 24 5 7 ined if and how Hu proteins function in the context of coupled transcription and splicing. Given that three of four Hu protein family members are almost exclusively expressed in neurons, we used mouse primary cerebellar neurons and neurons differen- tiated from mouse ES cells throughout our studies. These pri- D mary neurons and ES cell-derived neurons (ES neurons) have proven to be ideal systems for three reasons. First, two of the pre- viously characterized Hu protein targets, neurofibromatosis type 1 (NF1 for human and Nf1 for mouse) and apoptosis-promoting receptor Fas are endogenously expressed in mouse ES cells and in neurons differentiated from ES cells. Second, both alternative exons, exon 23a of Nf1 and exon 6 of Fas, are regulated differ- entially in neuronal cells with almost exclusive skipping of the alternative exon in neurons (Fig. 1 A–C; sequences of the two E F exons shown are in Fig. S1). Third, Hu proteins are abundantly expressed in neurons, as shown in Western blot and RT-PCR ana- lysis (Fig. 1D and Fig. S2B). Of the four Hu protein members, HuA/R is expressed in both ES cells and neurons, whereas the RNAPII other three members are significantly enriched in neurons RNAPII (Fig. 1D and Fig. S2B). It should be noted that the commercial anti-HuR antibody has cross-reactivity to HuB, HuC, and HuD (Fig. S2A) and therefore was used to detect expression of these neuron-specific Hu protein members. The C-terminal domain (CTD) of the largest subunit of G H RNAPII, Rbp1, consisting of multiple repeats of a heptamer se- quence, provides a crucial link between transcription and splicing (22, 28, 29).
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