Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition

Bhattacharya, Saikat; Workman, Jerry L.

doi:10.1186/s13072-020-00362-8

Cited by 25 publications

(45 citation statements)

References 42 publications

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“…Microscopy with the GFP-tagged version of the fragments revealed that both localized to the nucleus, which is consistent with our previous characterization of the SETD2 NLS (Fig. 2b ) 36 . Next, Halo-SETD2 1–1692 and 1404–2564 (SETD2C) were affinity-purified from 293T extracts using Halo ligand-conjugated magnetic resin.…”

Section: Resultssupporting

confidence: 91%

“…This fragment was nuclear, consistent with our previous characterization of the SETD2 NLS (Supplementary Fig. 3a ) 36 . Hence, the localization of this SETD2 fragment cannot explain the lack of interaction with hnRNP L, which is also nuclear.…”

Section: Resultssupporting

confidence: 91%

“…Next, Halo-FLAG-SETD2C with and without RNase treatment, and also Halo-FLAG-SETD2CΔSRI (the SRI domain is known to mediate the Set2-Pol II interaction) from 293T extracts were affinity-purified. Previously we have shown that the SETD2-Pol II interaction is not affected by RNase treatment and is abolished upon deletion of the SRI domain from SETD2 36 . Notably, the interaction with hnRNP L persisted without the Pol II interaction domain and in fact, increased upon RNase treatment (Fig.…”

Section: Resultsmentioning

confidence: 86%

“…Earlier we showed that SETD2 is an aggregate-prone protein 36 . We co-expressed mCherry-hnRNP L and GFP-SETD2C in 293T cells.…”

Section: Resultsmentioning

confidence: 92%

“…1g , Supplementary Data 1 ). Previously, we and others have shown that the full-length SETD2 protein is robustly degraded by the ubiquitin-proteasome pathway 36 , 37 . Therefore, the low dNSAF values of SETD2 could be due to the low abundance of the endogenous SETD2 protein.…”

Section: Resultsmentioning

confidence: 94%

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The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

et al. 2021

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Heterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP L in vitro and in vivo. This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2, by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.

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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 86%

“…Earlier we showed that SETD2 is an aggregate-prone protein 36 . We co-expressed mCherry-hnRNP L and GFP-SETD2C in 293T cells.…”

Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 94%

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The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

et al. 2021

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The lysine methyltransferase SETD2 is a dynamically expressed regulator of early neural crest development

Roffers-Agarwal

Lidberg

Gammill

2021

Genesis

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Summary SETD2 is a histone H3 lysine 36 (H3K36) tri‐methylase that is upregulated in response to neural crest induction. Because the H3K36 di‐methylase NSD3 and cytoplasmic non‐histone protein methylation are necessary for neural crest development, we investigated the expression and requirement for SETD2 in the neural crest. SetD2 is expressed throughout the chick blastoderm beginning at gastrulation. Subsequently, SetD2 mRNA becomes restricted to the neural plate, where it is strongly and dynamically expressed as neural tissue is regionalized and cell fate decisions are made. This includes expression in premigratory neural crest cells, which is downregulated prior to migration. Likely due to the early onset of its expression, SETD2 morpholino knockdown does not significantly alter premigratory Sox10 expression or neural crest migration; however, both are disrupted by a methyltransferase mutant SETD2 construct. These results suggest that SETD2 activity is essential for early neural crest development, further demonstrating that lysine methylation is an important mechanism regulating the neural crest.

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SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2’s role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an ‘epigenetic’ writer enzyme in normal cells and in disease.

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Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition

Cited by 25 publications

References 42 publications

The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain

The lysine methyltransferase SETD2 is a dynamically expressed regulator of early neural crest development

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

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