Disorders of histone methylation: Molecular basis and clinical syndromes

Ojaimi, Mode Al; Banimortada, Bashar J; Othman, Amna; Riedhammer, Korbinian; Almannai, Mohammed; El‐Hattab, Ayman W.

doi:10.1111/cge.14181

Cited by 8 publications

(5 citation statements)

References 70 publications

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“…Histone methylation is a key histone modification mode to regulate gene expression 34 . Histone methylation occurs mainly on lysine residues of histones H3 and H4 and is regulated by histone methyltransferase and demethylase 35,36 . H3K36‐dimethylation (H3K36me2) and H3K4‐trimethylation (H3K4me3) are widely recognized as key markers for the structure of chromatin 37 .…”

Section: Resultsmentioning

confidence: 99%

“…34 Histone methylation occurs mainly on lysine residues of histones H3 and H4 and is regulated by histone methyltransferase and demethylase. 35,36 H3K36-dimethylation (H3K36me2) and H3K4trimethylation (H3K4me3) are widely recognized as key markers for the structure of chromatin. 37 H3K36me2 mainly marks chromatin compaction and implicates gene repression, 38 while H3K4me3 is usually enriched at active chromatin regions and corresponded with actively transcribed genes.…”

Section: Chromosomal Histone Modification Of Macrophages On Micropatt...mentioning

confidence: 99%

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Suppression of LPS‐activated inflammatory responses and chromosomal histone modifications in macrophages by micropattern‐induced nuclear deformation

Chu,

Han,

et al. 2023

J Biomedical Materials Res

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Macrophages are important immune effector cells which participate various physiological and pathological conditions. Numerous studies have demonstrated the regulation of macrophage phenotype by micropatterns. It is well accepted that micropatterns affect cellular behaviors through changing cell shape and modulating the associated mechanical sensors on the plasma membrane and cytoskeleton. However, the role of nucleus, which serves as a critical physical sensing device, is often ignored. Herein, we found the nuclear deformation and the subsequently increased chromosomal histone methylation (H3K36me2) may contribute to the micropattern‐induced suppression of macrophage inflammatory responses. Specifically, macrophages on micropatterned surfaces expressed lower levels of key inflammatory genes, compared with those on flat surfaces. Further investigation on macrophage nuclei showed that micropatterned surfaces cause shrinkage of nucleus volume and compaction of chromatin. Moreover, micropatterned surfaces elevated the methylation level of H3K36me2 in macrophages, while decreased the methylation level of H3K4me3. Our study provides new mechanistic insight into how micropatterns affect macrophage phenotype and highlights the importance of nuclear shape and chromatin histone modification in mediating micropattern‐induced change in cell behaviors.

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Section: Resultsmentioning

confidence: 99%

Section: Chromosomal Histone Modification Of Macrophages On Micropatt...mentioning

confidence: 99%

Suppression of LPS‐activated inflammatory responses and chromosomal histone modifications in macrophages by micropattern‐induced nuclear deformation

Chu,

Han,

et al. 2023

J Biomedical Materials Res

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“…Future studies seeking to clarify this mechanism may reveal the commonalities among the spectrum of neurodevelopmental disorders associated with histones and histone lysine methyltransferases as well as demethylases (Ojaimi et al, 2022). We expect that better understanding the role of histones in the control of human development will be essential to discovering effective therapies.…”

Section: Discussionmentioning

confidence: 99%

“…associated with histones and histone lysine methyltransferases as well as demethylases (Ojaimi et al, 2022). We expect that better understanding the role of histones in the control of human development will be essential to discovering effective therapies.…”

Section: Author Contributionsmentioning

confidence: 99%

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome

Borja

Borjas-Mendoza

Bivona

et al. 2023

American J of Med Genetics Pt A

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Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4‐year‐old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease‐causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4‐associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

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“…In the early 1990s, it was proposed that histone gene transcription was enhanced during the early S phase of the cell cycle ( Stein et al 1994 ). Histone methylation is a stable and heritable epigenetic histone posttranslational modification, mainly occurring on lysine and arginine residues of histones H3 and H4 ( Al Ojaimi et al 2022 ). During the cell cycle, H3K9me3, H3K27me3, and H3K36me2 delimit the majority of the human genome into mutually unshared regions ( Van Rechem et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Decreased NSD2 impairs stromal cell proliferation in human endometrium via reprogramming H3K36me2

Qin,

Wei,

et al. 2024

Reproduction

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Recurrent implantation failure (RIF) is a formidable challenge in assisted reproductive technology because of its unclear molecular mechanism. Impaired human endometrial stromal cell (HESC) proliferation disrupts the rhythm of the menstrual cycle, resulting in devastating disorders between the embryo and the endometrium. The molecular function of histone methylation enzymes in modulating HESC proliferation remains largely uncharacterized. Herein, we found that the levels of histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) and the di-methylation of lysine 36 on histone H3 are decreased significantly in the proliferative-phase endometrium of patients with RIF. Knockdown of NSD2 in an HESC cell line markedly impaired cell proliferation and globally reduced H3K36me2 binding to chromatin, leading to altered expression of many genes. Transcriptomic analyses revealed that cell cycle-related gene sets were downregulated in the endometrium of patients with RIF and in NSD2 knockdown HESCs. Furthermore, RNA-sequencing and CUT&Tag-Sequencing analysis suggested that NSD2 knockdown reduced the binding of H3K36me2 to the promoter region of cell cycle marker gene MCM7 (encoding minichromosome maintenance complex component 7) and downregulated its expression. The interaction of H3K36me2 with the MCM7 promoter was verified using chromatin immunoprecipitation-quantitative real-time PCR. Our results demonstrated a unifying epigenome-scale mechanism by which decreased NSD2 impairs endometrial stromal cell proliferation in the proliferative-phase endometrium of patients with RIF.

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Disorders of histone methylation: Molecular basis and clinical syndromes

Cited by 8 publications

References 70 publications

Suppression of LPS‐activated inflammatory responses and chromosomal histone modifications in macrophages by micropattern‐induced nuclear deformation

Suppression of LPS‐activated inflammatory responses and chromosomal histone modifications in macrophages by micropattern‐induced nuclear deformation

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome

Decreased NSD2 impairs stromal cell proliferation in human endometrium via reprogramming H3K36me2

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