Impaired histone inheritance promotes tumor progression

Tian, Congcong; Zhou, Jiaqi; Li, Xinran; Gao, Yuan; Wen, Quan; Kang, Xing; Wang, N; Yao, Yuan; Jiang, Jianjuan; Song, Guibing; Zhang, Tianjun; Hu, Shouyang; Liao, Ji; Yu, Cheng-Rong; Wang, Zhi Quan; Liu, Xiangyu; Pei, Xin-Hai; Chan, Kui Ming; Liu, Zichuan; Gan, Haiyun

doi:10.1038/s41467-023-39185-y

Cited by 18 publications

(7 citation statements)

References 88 publications

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“…84 In a recent study, cells carrying mutations in MCM2, a protein associated with recycling of histones after DNA replication in eukaryotes, led to defects in differentiation and tumor progression in cell culture models due to impaired histone inheritance. 85,86 While here we used our recruitment system to study establishment and maintenance of epigenetic memory in the context of a particular cancer-causing histone mutation, our approach can be extended to study this phenomenon in other cancer types.…”

Section: Discussionmentioning

confidence: 99%

The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Sinha,

Nickels,

Thurm

et al. 2023

Preprint

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SummaryHistone H3.3 is frequently mutated in cancers, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the cellular epigenetic landscape, it remains unclear how it affects the dynamics of gene expression. Here, we use a synthetic reporter to measure the effect of H3.3K36M on silencing and epigenetic memory after recruitment of KRAB: a member of the largest class of human repressors, commonly used in synthetic biology, and associated with H3K9me3. We find that H3.3K36M, which decreases H3K36 methylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a new model for establishment and maintenance of epigenetic memory, where H3K36 methylation is necessary to convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

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Section: Discussionmentioning

confidence: 99%

The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Sinha,

Nickels,

Thurm

et al. 2023

Preprint

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“…CUT&Tag-qPCR was performed as previously reported with minor modifications (83). Briefly, the DNA products of CUT&Tag were divided, 6µL was used as “Input”, and the other 18µL undergoing library PCR amplification and purification was used as “IP products.” Finally, the “Input” and “IP products” were dilute 30 times for qPCR assay.…”

Section: Methodsmentioning

confidence: 99%

Distinct roles of H3K27me3 and H3K36me3 in vernalization response, maintenance and resetting in winter wheat

Liu,

Lin,

Deng

et al. 2023

Preprint

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Winter plants rely on vernalization, a vital process for adapting to cold and ensuring successful reproduction. However, understanding the role of histone modifications in guiding the vernalization process in winter wheat is limited. In this study, we investigate the transcriptome and chromatin dynamics in the shoot apex throughout the life cycle of winter wheat in the field. Two core histone modifications, H3K27me3 and H3K36me3, exhibit opposite pattern on the key vernalization geneVERNALIZATION1(VRN1), correlated with its induction during cold exposure. Additionally, H3K36me3 remains high atVRN1after cold exposure, maintaining its active state. Mutations in FERTILIZATION-INDEPENDENT ENDOSPERM (TaFIE) and SET DOMAIN GROUP 8 (TaSDG8), writer complex components of H3K27me3 and H3K36me3, respectively, affect flowering time. Interestingly,VRN1loses its high expression after cold exposure memory in the absence of H3K36me3. During embryo development,VRN1is silenced with the removal of H3K36me3 in both winter and spring alleles. H3K27me3 is selectively added to the winter allele, influencing the cold exposure requirement for the next generation. Integrating gene expression with H3K27me3 and H3K36me3 patterns identified potential regulators of flowering. This study reveals distinct roles of H3K27me3 and H3K36me3 in controlling vernalization response, maintenance, and resetting in winter wheat.Significance StatementVernalization, initially observed in cereals, lacks a comprehensive understanding of its underlying mechanism, particularly regarding chromatin-mediated transcriptional regulation in winter wheat. By delving into the transcriptome and chromatin dynamics in the shoot apex throughout winter wheat’s life cycle, we pinpointed two crucial histone modifications, H3K27me3 and H3K36me3, each playing distinct roles at different vernalization stages. H3K27me3 is implicated in establishing and resetting the extended cold exposure requirement for winter wheat, gradually diminishing during vernalization. On the other hand, H3K36me3 is crucial for maintainingVRN1’s active state post-cold exposure, contributing to the memory of the vernalization treatment. Additionally, the integration of transcriptome and histone modification profiles unveiled potential novel regulators of flowering in winter wheat.

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“…Symmetric histone recycling to the two replicated strands underlies the maintenance of cellular identity after cell division 4,14,18,21–23 . In contrast, asymmetric histone recycling alters gene expression profiles in the two daughter cells and potentially triggers cell differentiation 4,5,11,24 .…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of parental H3/H4 recycling at a replication fork

Nagae,

Murayama,

Terakawa

2024

Preprint

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In eukaryotic chromatin replication, faithful recycling of histones from parental DNA to replicated leading and lagging strands is essential for maintaining epigenetic information across generations. A recent experimental study has revealed that disrupting interactions between the N-terminal disordered tail of Mcm2, a subunit in DNA replication machinery, and a histone H3/H4 tetramer, a carrier of epigenetic modifications, perturbs their faithful recycling. However, the molecular pathways via which the H3/H4 tetramer attached to Mcm2 is recycled to the replicated strands have yet to be deciphered. Furthermore, the factors that regulate the ratio recycled to each strand and the destination location still need to be discovered. The elucidation requires visualization of a structural trajectory from H3/H4 bound to Mcm2 until recycled to the replicated strands. In this study, we performed molecular dynamics simulations of yeast DNA replication machinery (Mcm2-7, Cdc45, GINS, Pol ε, and RPA), an H3/H4 tetramer, and replicated DNA strands. The simulations demonstrated that histones are recycled via Cdc45-mediated and unmediated pathways even without histone chaperones, as ourin vitrobiochemical assays supported. Also, RPA binding to the ssDNA portion of the lagging strand regulated the ratio recycled to each strand, whereas DNA bending by Pol ε modulated the destination location. Together, the simulations in this study provided testable hypotheses, which are vital for clarifying intracellular histone recycling controlled by the cooperation of many histone chaperones.

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Impaired histone inheritance promotes tumor progression

Cited by 18 publications

References 88 publications

The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

The H3.3 K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

Distinct roles of H3K27me3 and H3K36me3 in vernalization response, maintenance and resetting in winter wheat

Molecular mechanism of parental H3/H4 recycling at a replication fork

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