Redesigning the Drosophila histone gene cluster: An improved genetic platform for spatiotemporal manipulation of histone function DOI
Aaron T. Crain, Markus Nevil,

Mary Leatham‐Jensen

и другие.

Genetics, Год журнала: 2024, Номер 228(1)

Опубликована: Июль 22, 2024

Mutating replication-dependent (RD) histone genes is an important tool for understanding chromatin-based epigenetic regulation. Deploying this in metazoans particularly challenging because RD histones these organisms are typically encoded by many genes, often located at multiple loci. Such gene arrangements make the ability to generate homogenous mutant genotypes site-specific editing quite difficult. Drosophila melanogaster provides a solution problem organized into single large tandem array that can be deleted and replaced with transgenes containing genes. In last ∼15 years several different replacement platforms were developed using simple strategy. However, each platform contains weaknesses preclude full use of powerful developmental genetic capabilities available researchers. Here we describe development newly engineered rectifies weaknesses. We used CRISPR precisely delete (HisC), replacing it multifunctional cassette permits insertion either one or two synthetic arrays selectable markers. designed selectively integrated specific tissues recombinases. also present method rapidly synthesizing any genotype Golden Gate cloning technologies. These improvements facilitate generation cells various stages provide opportunity apply forward strategies interrogate chromatin structure

Язык: Английский

Therapeutic targeting of BET bromodomain and other epigenetic acetylrecognition domain–containing factors DOI
Sarah Gold, Ali Shilatifard

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 86, С. 102181 - 102181

Опубликована: Апрель 2, 2024

Язык: Английский

Процитировано

5
Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges DOI Creative Commons
Sarah Gold, Ali Shilatifard

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(20)

Опубликована: Окт. 14, 2024

As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation the enzyme complexes represent a major frontier therapeutic development. Clinically viable targeting activities of methyltransferases (HKMT) demethylases (HKDMs) have only recently begun emerge following FDA approval EZH2 inhibitor tazemetostat in 2020 remain limited well-studied SET domain-containing HKMTs their opposing HKDMs. These include H3K27 EZH2/EZH1, singular H3K79 methyltransferase DOT1L, H3K4 MLL1/COMPASS well H3K9 H3K36 methyltransferases. They additionally H3K4/9-preferential demethylase LSD1 H3K4-, H3K27-, H3K36-preferential KDM5, KDM6, KDM2 subfamilies, respectively. This Review discusses results recent clinical preclinical studies relevant all these existing therapies. It provides an update on advancements development, more basic molecular understanding, within past 5 years approximately. also offers perspective departs from long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors proximity-based approaches rather than catalytic domain outlook future

Язык: Английский

Процитировано

5
Comprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD DOI Creative Commons
José M. Herranz, Amaya López-Pascual, Alex Clavería-Cabello

и другие.

Journal of Physiology and Biochemistry, Год журнала: 2023, Номер 79(4), С. 901 - 924

Опубликована: Авг. 25, 2023

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with complex etiology. Its incidence increasing globally in parallel the obesity epidemic, and it now considered most common Western countries. The precise mechanisms underlying development progression of NAFLD are still poorly understood. dysregulation epigenetic epitranscriptomic increasingly recognized to play pathogenic roles multiple conditions, including chronic diseases. Here, we have performed comprehensive analysis expression genes total 903 tissue samples corresponding patients normal liver, obese patients, non-alcoholic (NAFL) steatohepatitis (NASH), advancing stages progression. We integrated ten transcriptomic datasets an unbiased manner, enabling their robust comparison. describe complete landscape genes' along course disease. identify signatures significantly dysregulated association progression, particularly fibrosis development. Most these effectors not been previously described human NAFLD, altered may implications. also enzymes involved metabolism substrates cofactors effectors. This study provides novel information on pathogenesis guide identification drug targets treat this its towards hepatocellular carcinoma.

Язык: Английский

Процитировано

10
Regulation of adipogenesis by histone methyltransferases DOI Creative Commons
Yuanxiang Zhao,

Zachary Skovgaard,

Qinyi Wang

и другие.

Differentiation, Год журнала: 2024, Номер 136, С. 100746 - 100746

Опубликована: Янв. 14, 2024

Epigenetic regulation is a critical component of lineage determination. Adipogenesis the process through which uncommitted stem cells or adipogenic precursor differentiate into adipocytes, most abundant cell type adipose tissue. Studies examining chromatin modification during adipogenesis have provided further understanding molecular blueprint that controls onset differentiation. Unlike histone acetylation, methylation has context dependent effects on activity transcribed region DNA, with individual combined marks different residues providing distinct signals for gene expression. Over half 42 methyltransferases identified in mammalian been investigated their role adipogenesis, but across large body literature available, there lack clarity over potential correlations emerging patterns among players. In this review, we will summarize important findings from studies published past 15 years including both protein arginine (PRMTs) and lysine (KMTs). We reveal PRMT1/4/5, H3K4 KMTs (MLL1, MLL3, MLL4, SMYD2 SET7/9) H3K27 (EZH2) all play positive roles while PRMT6/7 H3K9 (G9a, SUV39H1, SUV39H2, SETDB1) negative adipogenesis.

Язык: Английский

Процитировано

4
Role of Histone Modifications in Kidney Fibrosis DOI Creative Commons

Shengyu Pan,

Tianhui Yuan,

Yuqi Xia

и другие.

Medicina, Год журнала: 2024, Номер 60(6), С. 888 - 888

Опубликована: Май 28, 2024

Chronic kidney disease (CKD) is characterized by persistent dysfunction, ultimately resulting in end-stage renal (ESRD). Renal fibrosis a crucial pathological feature of CKD and ESRD. However, there no effective treatment for this condition. Despite the complex molecular mechanisms involved fibrosis, increasing evidence highlights role histone modification its regulation. The reversibility modifications offers promising avenues therapeutic strategies to block or reverse fibrosis. Therefore, comprehensive understanding regulatory implications may provide novel insights into more safer approaches. This review recent advances particularly methylation acetylation. aim explore potential as targets treating

Язык: Английский

Процитировано

4
Drosophila melanogasterSet8 and L(3)mbt function in gene expression independently of histone H4 lysine 20 methylation DOI Open Access
Aaron T. Crain, Megan B Butler, Christina A. Hill

и другие.

Genes & Development, Год журнала: 2024, Номер unknown

Опубликована: Июнь 12, 2024

Monomethylation of lysine 20 histone H4 (H4K20me1) is catalyzed by Set8 and thought to play important roles in many aspects genome function that are mediated H4K20me binding proteins. We interrogated this model a developing animal comparing parallel the transcriptomes null , K20R/A l(3)mbt mutant Drosophila melanogaster . found gene expression profiles K20A K20R larvae markedly different than despite similar reductions H4K20me1. cells have severely disrupted transcriptome fail proliferate vivo, but these phenotypes not recapitulated mutation K20 indicating developmental defects animals largely due H4K20me1-independent effects on expression. Furthermore, H4K20me1 protein L(3)mbt recruited transcription start sites most genes independently even though bound high levels Moreover, both bind purified H4K20R nucleosomes vitro. conclude changes mutants cannot be explained loss or chromatin therefore does large role

Язык: Английский

Процитировано

4
Exploring the versatility of zygotic genome regulators: A comparative and functional analysis DOI Creative Commons
Ankita Sharma, Greg Jude Dsilva, Girish Deshpande

и другие.

Cell Reports, Год журнала: 2024, Номер 43(9), С. 114680 - 114680

Опубликована: Авг. 24, 2024

The activation of the zygotic genome constitutes an essential process during early embryogenesis that determines overall progression embryonic development. Zygotic (ZGA) is tightly regulated, involving a delicate interplay activators and repressors, to precisely control timing spatial pattern gene expression. While regulators ZGA vary across species, they accomplish comparable outcomes. Recent studies have shed light on unanticipated roles components both after ZGA. Moreover, different seem acquired unique functional modalities manifest their regulatory potential. In this review, we explore these observations assess whether are simply anecdotal or contribute broader framework employs versatile means arrive at conserved outcome.

Язык: Английский

Процитировано

4
Basic Epigenetic Mechanisms DOI
James Davie, Hedieh Sattarifard, S Sudhakar

и другие.

Sub-cellular biochemistry/Subcellular biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 49

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Orthologous transcription factor replacement reveals that stable TFIIIC complexes are required for proper mitotic chromosome segregation DOI Creative Commons

Akshi Gupta,

Po‐Chen Hsu,

Richard Ron R. Litan

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Abstract Transcription factors are speculated to play crucial roles in adaptive evolution. Using ortholog replacement of essential transcription (eTFs) from other yeast species, we investigated how eTFs can change. Several orthologs could not fully complement Saccharomyces cerevisiae mutants, indicating that functions or interactions these have changed, rendering them incompatible. We further characterized TFIIIC, a fast-evolving protein complex assists RNA polymerase III-mediated transcription, which exhibited complete partial incompatibility several subunits. In the orthologous Tfc7-replacement line, binding TFIIIC tRNA genes was reduced, yet abundance severely affected. However, chromosomes cells were often mis-segregated during mitosis and their fitness reduced spindle checkpoint mutant. Our chromatin-immunoprecipitation experiments uncovered unstable results defective cohesion loading, leading chromosome mis-segregation. Swapping highly divergent C-terminal domain Tfc7 rescued its interaction with Tfc1 cell fitness, supporting is caused by altered between reveal distinct well-studied complex.

Язык: Английский

Процитировано

0
Moonlighting Proteins of Human and Some Other Eukaryotes. Evolutionary Aspects DOI
Shishkin Ss

Biochemistry (Moscow), Год журнала: 2025, Номер 90(S1), С. S36 - S59

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0