Review

Authors: Joshua C Black, Capucine Van Rechem, Johnathan R Whetstine...

Histone lysine methylation has emerged as a critical player in the regulation of gene expression, cell cycle, genome stability, and nuclear architecture. Over the past decade, a tremendous amount of progress has led to the characterization of methyl modifications and the lysine methyltransferases (KMTs) and lysine demethylases (KDMs) that regulate them. Here, we review the discovery and characterization of the KMTs and KDMs and the methyl modifications they regulate. We discuss the localization of the KMTs and KDMs as well as the distribution of lysine methylation throughout the genome. We highlight how these data have shaped our view of lysine methylation as a key determinant of complex chromatin states. Finally, we discuss the regulation of KMTs and KDMs by proteasomal degradation, posttranscriptional mechanisms, and metabolic status. We propose key questions for the field and highlight areas that we predict will yield exciting discoveries in the years to come.

Topics: Animals; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Methylation

PubMed: 23200123
DOI: 10.1016/j.molcel.2012.11.006

Review

Authors: Marta Andrés, Daniel García-Gomis, Inma Ponte...

Histone H1 is the most variable histone and its role at the epigenetic level is less characterized than that of core histones. In vertebrates, H1 is a multigene family, which can encode up to 11 subtypes. The H1 subtype composition is different among cell types during the cell cycle and differentiation. Mass spectrometry-based proteomics has added a new layer of complexity with the identification of a large number of post-translational modifications (PTMs) in H1. In this review, we summarize histone H1 PTMs from lower eukaryotes to humans, with a particular focus on mammalian PTMs. Special emphasis is made on PTMs, whose molecular function has been described. Post-translational modifications in H1 have been associated with the regulation of chromatin structure during the cell cycle as well as transcriptional activation, DNA damage response, and cellular differentiation. Additionally, PTMs in histone H1 that have been linked to diseases such as cancer, autoimmune disorders, and viral infection are examined. Future perspectives and challenges in the profiling of histone H1 PTMs are also discussed.

Topics: Animals; Chromatin Assembly and Disassembly; Histone Code; Histones; Humans; Protein Processing, Post-Translational

PubMed: 32824860
DOI: 10.3390/ijms21165941

Authors: Asifa Akhtar

Q&A with Asifa Akhtar who studies histone acetylation and genome regulation.

Topics: Histones; Genome; Acetylation

PubMed: 37098326
DOI: 10.1016/j.cub.2023.03.040

Authors: Fjodor Merkuri, Megan Rothstein, Marcos Simoes-Costa...

Embryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.

Topics: Histones; Gene Regulatory Networks; Transcription Factors; Embryonic Development; Mesoderm

PubMed: 38167340
DOI: 10.1038/s41467-023-44121-1

Authors: Jingwen Yang, Lingxin Zhu, Haichun Pan...

Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis. Elevated BMP signaling in CNCCs through constitutively activated ACVR1 (ca-ACVR1) suppressed glycolytic activity and blocked lactate production via a p53-dependent process that resulted in severe midline facial defects. By modulating epigenetic remodeling, BMP signaling-dependent lactate generation drove histone lactylation levels to alter essential genes of Pdgfra, thus regulating CNCC behavior in vitro as well as in vivo. These findings define an axis wherein BMP signaling controls a metabolic/epigenetic cascade to direct craniofacial morphogenesis, thus providing a conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryonic development. These findings indicate potential preventive strategies of congenital craniofacial birth defects via modulating metabolic-driven histone lactylation.

Topics: Animals; Humans; Epigenesis, Genetic; Face; Histones; Lactates; Mammals; Morphogenesis; Neural Crest

PubMed: 38466355
DOI: 10.1172/JCI165787

Review

Authors: Dongbo Ding, Thi Thuy Nguyen, Matthew Y H Pang...

Canonical histones (H2A, H2B, H3, and H4) are present in all eukaryotes where they package genomic DNA and participate in numerous cellular processes, such as transcription regulation and DNA repair. In addition to the canonical histones, there are many histone variants, which have different amino acid sequences, possess tissue-specific expression profiles, and function distinctly from the canonical counterparts. A number of histone variants, including both core histones (H2A/H2B/H3/H4) and linker histones (H1/H5), have been identified to date. Htz1 (H2A.Z) and CENP-A (CenH3) are present from yeasts to mammals, and H3.3 is present from to humans. In addition to the prevalent variants, others like H3.4 (H3t), H2A.Bbd, and TH2B, as well as several H1 variants, are found to be specific to mammals. Among them, H2BFWT, H3.5, H3.X, H3.Y, and H4G are unique to primates (or Hominidae). In this review, we focus on localization and function of primate- or hominidae-specific histone variants.

Topics: Amino Acid Sequence; Animals; Brain; Breast Neoplasms; Cell Nucleolus; DNA; Gene Expression Regulation; Histones; Humans; Mammals; Phylogeny; Primates

PubMed: 33245240
DOI: 10.1139/gen-2020-0094

Review

Authors: Bing Zhu, Danny Reinberg

"Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. Here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information.

Topics: Epigenesis, Genetic; Histones; Methylation; Mitosis; Models, Genetic

PubMed: 21321606
DOI: 10.1038/cr.2011.26

Review

Authors: Kun Li, Ziqiang Wang

Histone crotonylation is a recently described post-translational modification that occurs at multiple identified histone lysine crotonylation sites. An increasing number of studies have demonstrated that histone crotonylation at DNA regulatory elements plays an important role in the activation of gene transcription. However, among others, we have shown that elevated cellular crotonylation levels result in the inhibition of endocytosis-related gene expression and pro-growth gene expression, implicating the complexity of histone crotonylation in gene regulation. Therefore, it is important to understand how histone crotonylation is regulated and how it, in turn, regulates the expression of its target genes. In this review, we summarize the regulatory factors that control histone crotonylation and discuss the role of different histone crotonylation sites in regulating gene expression, while providing novel insights into the central role of histone crotonylation in gene regulation.

Topics: Gene Expression Regulation; Histones; Lysine; Protein Processing, Post-Translational

PubMed: 33549150
DOI: 10.1186/s13072-021-00385-9

Review

Authors: Sam Alsford, David Horn

The histones are responsible for packaging and regulating access to eukaryotic genomes. Trypanosomatids are flagellated protists that diverged early from the eukaryotic lineage and include parasites that cause disease in humans and other mammals. Here, we review the properties of histones in parasitic trypanosomatids, from gene organization and sequence to expression, post-translational modification and function within chromatin. Phylogenetic and experimental analysis indicates that certain specifically conserved histone sequence motifs, particularly within the N-terminal 'tail' domains, possibly represent functionally important modification substrates conserved throughout the eukaryotic lineage. For example, histone H3 contains a highly conserved methylation substrate. Trypanosomatids also possess at least three variant histones. Among these is an orthologue of H2A.Z, a histone involved in protecting 'active' chromatin from silencing in yeast. Histones provide docking platforms for a variety of regulatory factors. The presence of histone modification and variant histones in trypanosomatids therefore represents evidence for a network that provides the discrimination required to regulate transcription, recombination, repair and chromosome replication and segregation.

Topics: Animals; Chromosome Segregation; Conserved Sequence; DNA Repair; DNA Replication; Gene Expression Regulation; Gene Silencing; Histones; Phylogeny; Protein Structure, Tertiary; Recombination, Genetic; Trypanosomatina

PubMed: 15228519
DOI: 10.1111/j.1365-2958.2004.04151.x

Authors: Congcong Tian, Jiaqi Zhou, Xinran Li...

Faithful inheritance of parental histones is essential to maintain epigenetic information and cellular identity during cell division. Parental histones are evenly deposited onto the replicating DNA of sister chromatids in a process dependent on the MCM2 subunit of DNA helicase. However, the impact of aberrant parental histone partition on human disease such as cancer is largely unknown. In this study, we construct a model of impaired histone inheritance by introducing MCM2-2A mutation (defective in parental histone binding) in MCF-7 breast cancer cells. The resulting impaired histone inheritance reprograms the histone modification landscapes of progeny cells, especially the repressive histone mark H3K27me3. Lower H3K27me3 levels derepress the expression of genes associated with development, cell proliferation, and epithelial to mesenchymal transition. These epigenetic changes confer fitness advantages to some newly emerged subclones and consequently promote tumor growth and metastasis after orthotopic implantation. In summary, our results indicate that impaired inheritance of parental histones can drive tumor progression.

Topics: Humans; Histones; Epithelial-Mesenchymal Transition; Epigenesis, Genetic; DNA Helicases; Histone Code

PubMed: 37301892
DOI: 10.1038/s41467-023-39185-y