The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications

Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.

Role of histone methylation in the development of multiple myeloma / 中国肿瘤临床

Multiple myeloma (MM) is a malignant clonal disease of the plasma cells in bone marrow. Despite the progress of MM treatment, almost all patients will relapse or become resistant to the prescribed drugs. As such, new treatment targets are urgently needed. As well as genetic defects and bone marrow microenvironment disorders, increasing evidence shows that epigenetic regulation plays an important role in MM. Studies have shown that mutations in epigenetic factors are often related to genomic instability, drug resistance and disease progression. These mutations have been found to increase after treatment, particularly histone methylation and DNA methylation modifying enzymes. Here, we reviewed the progress in histone methylation modification in MM, in particular the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) in the development of MM.

Wiedemann-Steiner syndrome with a novel pathogenic variant in KMT2A: a case report / Síndrome de Wiedemann-Steiner por una nueva variante patogénica en KMT2A: reporte de un caso

Abstract Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

Resumen Descripción del caso: Se reporta el caso de una paciente femenina de un año de edad, diagnosticada con Síndrome de Wiedemann-Steiner basado en la identificación de una nueva variante patogénica de novo de tipo frameshift en el gen KMT2A Mediante secuenciación de exoma usando el enfoque de trio, sumado a sus características clínicas. Hallazgos clínicos: las mutaciones en KMT2A causan el Síndrome de Wiedemann-Steiner, un desorden genético muy raro caracterizado por hipertricosis congénita, talla baja, retardo mental variable y fenotipo facial distintivo, los cuales se encuentran en la paciente reportada. Resultado: La Secuenciación de exoma completo encontró una variante de tipo frameshift: c.4177dupA (p. Ile1393Asnfs * 14) en KMT2A, este cambio a nivel génico genera una alteración de la unión específica a motivos CpG no metilados del DNA a la proteína. El genotipo y el fenotipo de la paciente fue comparado con los pacientes reportados previamente en la literatura. Relevancia clínica: En enfermedades con baja frecuencia como la aquí reportada es necesario establecer correlaciones genotipo-fenotipo que permitan establecer planes terapéuticos y de seguimiento. El análisis realizado no evidenció diferencias atribuibles a sexo o edad entre los pacientes diagnosticados con Síndrome de Weidemann-Steiner. La secuenciación de exoma permitió identificar causalidad en este caso, cuya característica principal de hipertricosis se asocia con alta heterogeneidad clínica y genética.

Effect of regulating endoplasmic reticulum stress on the expression of SET7/9 in the kidneys of db/db mice with diabetic nephropathy / 中华肾脏病杂志

Objective To investigate the effect and significance of regulating endoplasmic reticulum stress on the expression of histone methyltransferases SET7/9 in the kidneys of db/db mice.Methods Db/db mice were randomly divided into two groups according to random number table method:diabetic nephropathy model group (DN group,n=18) and betaine treatment group (DN+B group,n =18),db/m mice were defined as normal control group (NC group,n =18).At the end of 4,8 and 12 weeks,the expression of GRP78,SET7/9,H3K4me2,and monocyte chemoattractant protein 1 (MCP-1) was determined by real-time fluorescence PCR and Western blotting.24-hour urinary protein excretion rate (UPER) and urine MCP-1 were measured by enzyme linked immunosorbent assay (ELISA).The dynamic changes of blood glucose(BG),serum creatinine (Scr),blood urea nitrogen (BUN) were tested by completely automatic biochemistry analyzer.The morphology of kidney was estimated by special staining of periodic acid-schiff (PAS).Results The levels of BG,BUN,UAER and MCP-1 were significantly higher in DN group than those in NC group (P ＜ 0.05),and were in time-dependent manner.Glomerular basement membrane thickening and mesangial cells proliferation began to emerge in DN group at the end of week 4 and mesangial matrix expansion was more obvious at the end of week 12.The mRNA and protein expression of GRP78 and SET7/9 were elevated significantly in DN group as compared to NC group.The H3K4me2 protein expression level was also increased in time-dependent manner.Compared with the DN group,in DN+B group glomerular lesions attenuated and the GRP78 and SET7/9 expression levels obviously decreased (P ＜ 0.05).Furthermore,the levels of BG,BUN,UPER,MCP-1,H3K4me2 in DN+B group were also reduced (P ＜ 0.05).Conclusion Endoplasmic reticulum stress may be the upstream mechanism of mediating the expression of SET7/9 in the kidneys of DN mice.