Reading the chromatinized genome

Michael, Alicia K.; Thomä, Nicolas H.

doi:10.1016/j.cell.2021.05.029

Cited by 66 publications

(34 citation statements)

References 100 publications

(146 reference statements)

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“…These orthologs of the reprogramming factors included in our study were able to remodel nucleosomes more efficiently when nucleosome occupancy was high, suggesting that the proper positioning of nucleosomes can be a contributor to pioneer activity (Miao et al, 2022). Specific nucleosome positions may arrange the binding site of the pioneer factor such that it can be bound more efficiently (Michael and Thomä, 2021).…”

Section: Discussionmentioning

confidence: 99%

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Maresca

Brand

et al. 2022

Preprint

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Genome-wide transcriptional activity involves the binding of many transcription factors to thousands of sites in the genome. Determining which sites are directly driving transcription remains a challenge. Here we use acute protein depletion of the pioneer transcription factors OCT4 and SOX2 to establish their functionality in maintaining chromatin accessibility. We show that thousands of accessible sites are lost within an hour of protein depletion, indicating rapid turnover of these sites in the absence of pioneer factors. To understand the relationship with transcription we performed nascent transcription analysis and found that open chromatin sites that are maintained by SOX2 are highly predictive of gene expression, in contrast to SOX2 binding sites that do not maintain accessibility. We use CRISPR-Cas9 genome editing in the Klf2 locus to functionally validate a predicted regulatory element. We conclude that the regulatory activity of SOX2 is exerted largely at sites where it maintains accessibility and that other binding sites are largely dispensable for gene regulation.

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Section: Discussionmentioning

confidence: 99%

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Maresca

Brand

et al. 2022

Preprint

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“…A critical layer of control for these processes is the post-translational modification of histone proteins. Histone post-translational modifications (PTMs) can directly influence the structure of chromatin, for example by neutralizing the positive charge of histone proteins, or act as a docking site for so called chromatin ‘reader’ proteins (for reviews see [ 24 , 141 , 176 , 223 ]). Already early on it has been hypothesized that histone PTMs directly control chromatin processes and that a specific combination of histone PTMs can be viewed as a ‘code’ that specifies the function of a DNA region [ 177 ].…”

Section: Introductionmentioning

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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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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“…The results showed that only two InDel loci and four CNV loci were polymorphic in SBWC goats, whereas other loci exhibited only a single mutation type. Despite the fact that all variants are located in intronic regions, the mutations are located at non-coding regions on chromosomes may affect the binding of transcription factors ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Goat SNX29: mRNA expression, InDel and CNV detection, and their associations with litter size

Wang

et al. 2022

Front. Vet. Sci.

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The sorting nexin 29 (SNX29) gene, a member of the SNX family, is associated with material transport and lipid metabolism. Previous studies have shown that lipid metabolism affects reproductive function in animals. Thus, we hypothesized there is a correlation between the SNX29 gene and reproductive trait. To date, studies on the relationship between the SNX29 gene and reproductive traits are limited. Therefore, the purpose of this study was to examine the polymorphism in the SNX29 gene and its correlation with litter size. Herein, the mRNA expression levels of SNX29 were assayed in various goat tissue. Surprisingly, we found that SNX29 was highly expressed in the corpus luteum, large and small follicles. This result led us to suggest that the SNX29 gene has a critical role in reproduction. We further detected potential polymorphisms in Shaanbei white cashmere (SBWC) goats, including insertion/deletion (InDel, n = 2,057) and copy number variation (CNV, n = 1,402), which were related to fertility. The 17 bp deletion (n = 1004) and the 20 bp deletion (n = 1,053) within the SNX29 gene were discovered to be significantly associated with litter size (P < 0.05), and individuals the ID genotype of P1-Del-17 bp and the DD genotype of P2-Del-20bp had larger litter size. Additionally, the four CNV loci had significant correlations with litter size (P < 0.01) in our detected population. In CNV5, individuals with the median genotype were superior compared to those with loss or gain genotype in term of litter size, and in other three CNVs showed better reproductive trait in the gain genotype. Briefly, these findings suggest that SNX29 could be used as a candidate gene for litter size in goat breeding through marker-assisted selection (MAS).

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Reading the chromatinized genome

Cited by 66 publications

References 100 publications

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

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

Goat SNX29: mRNA expression, InDel and CNV detection, and their associations with litter size

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