Search

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment., This research project was supported by the national grants RTI2018-094005-B-I00 and BFU2015-66559-P from FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación (to M.B.); PI09/00751, PI10/02082, and PI13/02340 from the Instituto de Salud Carlos III (to C.A.); the MECD fellowship FPU14/06542 (to D.C.); AGAUR 2019 FI_B01024 and 2022 FI_B00528 fellowships (to J.C.-R. and A.D.R.-A., respectively); and predoctoral fellowships BES-2016-077251 (to M.-M.L.P.) and PRE2019-088529 (to O.M.). Research in the M.B. lab is further supported by the following grants: the Marie Skłodowska Curie Training network “INTERCEPT-MDS” H2020-MSCA-ITN-2020-953407 (to M.B.); MINECO-ISCIII PIE16/00011 (to M.B.); the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to M.B.); AGAUR 2017-SGR-305 (to M.B.); and Fundació La Marató de TV3 257/C/2019 (to M.B.). C.A.’s research has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 668596 (ChiLTERN) and 826121 (iPC) as well as from CIBERehd (CB06/04/0033) and AGAUR (2017-SGR-490). C.A. was supported by Ramón y Cajal (RYC-2010-07249) of the Ministry of Science and Innovation of Spain. Research at the IJC is supported by the “La Caixa” Foundation, the Fundació Internacional Josep Carreras, Celgene Spain, and the CERCA Programme/Generalitat de Catalunya.

This work was supported by the shared grant of Fundació La Marató de TV3 257/C/2019 to M.B. and F.H.H. and a predoctoral research fellowship from MCIU to O.M. (PRE2019-088529). Research in the Buschbeck lab is further supported by the following grants: MINECO grant RTI2018-094005-B-I00, the Marie Skłodowska Curie Training network 'INTER-CEPT-MDS' H2020-MSCA-ITN-2015-953407, AGAUR 2017-SGR-305, MINECO-ISCIII PIE16/00011 and the Deutsche José Car-reras Leukämie Stiftung DJCLS 14R/2018. Research at the IJC is generously supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Pro-gramme/Generalitat de Catalunya. The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are partic-ular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context-and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.

Simple Summary The structural unit of chromatin is the nucleosome that is composed of DNA wrapped around a core of eight histone proteins. Histone variants can replace 'standard' histones at specific sites of the genome. Thus, histone variants modulate all functions in the context of chromatin, such as gene expression. Here, we provide a concise review on a group of histone variants termed macroH2A. They contain two additional domains that contribute to their increased size. We discuss how these domains mediate molecular functions in normal cells and the role of macroH2As in gene expression and cancer. The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.

Altres ajuts: Research leading to inventions at the IJC is supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya. Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.