Whole-genome sequencing data mining efforts have revealed numerous histone mutations in a wide range of cancer types. These occur in all four core histones in both the tail and globular domains and remain largely uncharacterized. Here we used two high-throughput approaches, a DNA-barcoded mononucleosome library and a humanized yeast library, to profile the biochemical and cellular effects of these mutations. We identified cancer-associated mutations in the histone globular domains that enhance fundamental chromatin remodeling processes, histone exchange and nucleosome sliding, and are lethal in yeast. In mammalian cells, these mutations upregulate cancer-associated gene pathways and inhibit cellular differentiation by altering expression of lineage-specific transcription factors. This work represents a comprehensive functional analysis of the histone mutational landscape in human cancers and leads to a model in which histone mutations that perturb nucleosome remodeling may contribute to disease development and/or progression.

Oncohistone mutations enhance chromatin remodeling and alter cell fates.

Contributions of Histone Variants in Nucleosome Structure and Function.

The oncogenic role of histone mutations is one of the most relevant discovery in cancer epigenetics Recurrent mutations targeting histone genes have been described in pediatric brain tumors, chondroblastoma, giant cell tumor of bone and other tumor types The demonstration that mutant histones can be oncogenic and drive the tumorigenesis in pediatric tumors, led to the coining of the term “oncohistones” The first identified histone mutations were localized at or near residues normally targeted by post-translational modifications (PTMs) in the histone N-terminal tails and suggested a possible interference with histone PTMs regulation and reading In this review, we describe the peculiar organization of the multiple genes that encode histone proteins, and the latter advances in both the identification and the biological role of histone mutations in cancer Recent works show that recurrent somatic mutations target both N-terminal tails and globular histone fold domain in diverse tumor types Oncohistones are often dominant-negative and occur at higher frequencies in tumors affecting children and adolescents Notably, in many cases the mutations target selectively only some of the genes coding the same histone protein and are frequently associated with specific tumor types or, as documented for histone variant H33 in pediatric glioma, with peculiar tumors arising from specific anatomic locations The overview of the most recent advances suggests that the oncogenic potential of histone mutations can be exerted, together with the alteration of histone PTMs, through the destabilization of nucleosome and DNA–nucleosome interactions, as well as through the disruption of higher-order chromatin structure However, further studies are necessary to fully elucidate the mechanism of action of oncohistones, as well as to evaluate their possible application to cancer classification, prognosis and to the identification of new therapies

/pdf/the-dark-side-of-histones-genomic-organization-and-role-of-3qm8degh4t.pdf

The dark side of histones: genomic organization and role of oncohistones in cancer.

Identification of cancer driver mutations that confer a proliferative advantage is central to understanding cancer; however, searches have often been limited to protein-coding sequences and specific non-coding elements (for example, promoters) because of the challenge of modeling the highly variable somatic mutation rates observed across tumor genomes. Here we present Dig, a method to search for driver elements and mutations anywhere in the genome. We use deep neural networks to map cancer-specific mutation rates genome-wide at kilobase-scale resolution. These estimates are then refined to search for evidence of driver mutations under positive selection throughout the genome by comparing observed to expected mutation counts. We mapped mutation rates for 37 cancer types and applied these maps to identify putative drivers within intronic cryptic splice regions, 5' untranslated regions and infrequently mutated genes. Our high-resolution mutation rate maps, available for web-based exploration, are a resource to enable driver discovery genome-wide. 

/pdf/genome-wide-mapping-of-somatic-mutation-rates-uncovers-11ykfaww.pdf

Genome-wide mapping of somatic mutation rates uncovers drivers of cancer

Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation.

https://scholars.cityu.edu.hk/files/78104008/1_s2.0_S0021925821001460_main.pdf

The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer

Publication details: Wan, Y. C. E., Leung, T. C. S., Ding, D., Sun, X., Liu, J., Zhu, L., Kang, T. Z. E., Yang, D., Zhang, Y., Zhang, J., Qian, C., Huen, M. S. Y., Li, Q., Chow, M. Z. Y., Zheng, Z., Han, J., Goel, A., Wang, X., Ishibashi, T., & Chan, K. M. (2020). Cancer-associated histone mutation H2BG53D disrupts DNA-histone octamer interaction and promotes oncogenic phenotypes. Signal Transduction and Targeted Therapy, 5, [27]. https://doi.org/10.1038/s41392-020-0131-0

/pdf/cancer-associated-histone-mutation-h2bg53d-disrupts-dna-tan98uqoho.pdf

Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes

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The elevated transcription of ADAM19 by the oncohistone H2BE76K contributes to oncogenic properties in breast cancer

Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes