Histone exchange is associated with activator function at transcribed promoters and with repression at histone loci

Kassem, Sari; Ferrari, Paolo; Hughes, Amanda L.; Soudet, Julien; Rando, Oliver J.; Strubin, Michel

doi:10.1126/sciadv.abb0333

Cited by 10 publications

(14 citation statements)

References 60 publications

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“…Alternatively, it could be hypothesized that the cryptic transcription initiation itself in gene bodies in set2 knockout yeast cells is responsible for the increased histone turnover rate. In support of this, it has recently been found in budding yeast that histone turnover in promoter regions is mediated by transcriptional activators [ 93 , 207 ]. However, because transcriptional activators often directly recruit HATs to promoters, it is difficult to functionally separate transcription initiation from histone acetylation.…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 93%

“…However, because transcriptional activators often directly recruit HATs to promoters, it is difficult to functionally separate transcription initiation from histone acetylation. Interestingly, it has also been shown that H3K9 and H3K14, two lysine residues that are often acetylated in active genes, do not affect histone turnover suggesting that histone acetylation does not directly stimulate histone turnover [ 58 , 93 ]. However, it could be argued that many residues on H3 and H4 (as well as H2A/H2B) are acetylated during (cryptic) transcription initiation, all of which might contribute to histone turnover.…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

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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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Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 93%

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

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

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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“…For these genes, there was a regularity in the heatmaps pattern revealed ( Figure 15 ), which is possible evidence of AIPL1 involvement in shelterin complex regulation. The role of the shelterin complex, specifically its member RAP1, in global control of histone gene expression was confirmed in several studies [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 81%

RNA-Seq Analysis of Trans-Differentiated ARPE-19 Cells Transduced by AAV9-AIPL1 Vectors

Galieva,

Egorov,

Malogolovkin

et al. 2023

IJMS

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Inherited retinal disorders (IRD) have become a primary focus of gene therapy research since the success of adeno-associated virus-based therapeutics (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2). Dozens of monogenic IRDs could be potentially treated with a similar approach using an adeno-associated virus (AAV) to transfer a functional gene into the retina. Here, we present the results of the design, production, and in vitro testing of the AAV serotype 9 (AAV9) vector carrying the codon-optimized (co) copy of aryl hydrocarbon receptor-interacting protein like-1 (AIPL1) as a possible treatment for LCA4. The pAAV-AIPL1co was able to successfully transduce retinal pigment epithelium cells (ARPE-19) and initiate the expression of human AIPL1. Intriguingly, cells transduced with AAV9-AIPL1co showed much less antiviral response than AAV9-AIPL1wt (wild-type AIPL1) transduced. RNA-sequencing (RNA-seq) analysis of trans-differentiated ARPE-19 cells transduced with AAV9-AIPL1co demonstrated significant differences in the expression of genes involved in the innate immune response. In contrast, AAV9-AIPL1wt induced the prominent activation of multiple interferon-stimulated genes. The key part of the possible regulatory molecular mechanism is the activation of dsRNA-responsive antiviral oligoadenylate synthetases, and a significant increase in the level of histone coding genes’ transcripts overrepresented in RNA-seq data (i.e., H1, H2A, H2B, H3, and H4). The RNA-seq data suggests that AAV9-AIPL1co exhibiting less immunogenicity than AAV9-AIPL1wt can be used for potency testing, using relevant animal models to develop future therapeutics for LCA4.

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“…Since canonical nucleosomes have pseudo two‐fold symmetry, the central nucleosome dyad is considered to be the center of the protected ∼146 bp DNA fragment. However, histone‐DNA interactions are continually disrupted, particularly during transcription, DNA repair, and DNA recombination, where canonical histones can be swapped out with histone variants (Henikoff & Ahmad, 2005; Kassem et al., 2020; Talbert & Henikoff, 2014; Venkatesh & Workman, 2015). Even without full disruption, nucleosomes can transiently unwrap from one or both sides (Li, Levitus, Bustamante, & Widom, 2005).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Mapping of Nucleosome Positions at Base‐Pair Resolution Using Ortho‐Phenanthroline

Kondalaji

Bowman

2022

Current Protocols

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The positions of nucleosomes along genomic DNA play a role in defining patterns of gene expression and chromatin organization. Determination of nucleosome positions in vivo and in vitro, as revealed by the locations of histones on DNA, has provided insight into mechanisms of nucleosome sliding, spacing, assembly, and disassembly. Here, we describe methods for the in vitro determination of histone-DNA contacts at base-pair (bp) resolution. The protocol involves the labeling of histones with ortho-phenanthroline (OP), site-specific cleavage of nucleosomal DNA, and processing and analysis of the resulting DNA fragments. This methodology provides an efficient and high-resolution means for studying kinetics and behavior of enzymes that alter nucleosome structure and/or positioning, and can be used to identify preferred distributions of nucleosomes on natural DNA sequences.

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Histone exchange is associated with activator function at transcribed promoters and with repression at histone loci

Cited by 10 publications

References 60 publications

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

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

RNA-Seq Analysis of Trans-Differentiated ARPE-19 Cells Transduced by AAV9-AIPL1 Vectors

In Vitro Mapping of Nucleosome Positions at Base‐Pair Resolution Using Ortho‐Phenanthroline

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