Abstract 3768: Epigenetic dysregulation from chromosomal transit in micronuclei

Abstract

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei, and subsequent micronuclear envelope rupture profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and nontransformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer. Citation Format: Albert S. Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eleonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum. Epigenetic dysregulation from chromosomal transit in micronuclei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3768.

Pauperization of Emerin from nuclear envelope during chromatin bridge resolution drives prostate cancer cell migration and invasiveness

“…Surprisingly, another LEM-domain containing protein, LAP2α (Brachner & Foisner, 2014), was found with the same occurrence in both MN types (Fig.2C-D). Similarly, a lysine tri-methylation on histone H3 (H3K27me3), often enriched in MN (Agustinus et al , 2023), was also found with the same frequency in both MN types. Taken together, the collected data suggested that EMD level can differentiate MN into two fractions.…”

“…2C-D). Similarly, a lysine tri-methylation on histone H3 (H3K27me3), often enriched in MN (Agustinus et al, 2023), was also found with the same frequency in both MN types. Taken together, the collected data suggested that EMD level can differentiate MN into two fractions.…”

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations

“…This increases genomic instability, as shown by micronuclei accumulation. To identify these small DNA-containing cytoplasmic structures in vivo, we used known micronuclei markers such as DAPI/LAMIN A/C staining, γH2AX, and H3K27Me3 ( 33 , 34 ). Arid1a null hepatocytes show profound nuclear envelope malformations, characterized by the presence of deep invaginations, nuclear inclusions, and membrane bending and blebbing (fig.…”

CDK4 and CDK6 upregulation promotes DNA replication stress, genomic instability and resistance to EGFR targeted therapy in lung cancer

“…First, we analyzed tumor DNA through WES or targeted exome sequencing, potentially masking the detection of sub-clonal populations with low abundance and limiting the analysis to the coding DNA regions. Copy number fluctuation of trans- and cis-intronic regulatory elements might also contribute to the evolution of TKI resistance in CDK4/6 amp, EGFRmt NSCLC and will be a subject of future analyses 49 . We also limited our investigation to canonical roles of CDK4/6 as cell cycle regulators, whereas their functions in regulating gene expression, cell metabolism and immune editing 50 will be further evaluated in expanded clinical cohorts, including other cancer types.…”