Chromatin Mechanisms Driving Cancer

Abstract

The change in cell state from normal to malignant is driven fundamentally by oncogenic mutations in cooperation with epigenetic alterations of chromatin. These alterations in chromatin can be a consequence of environmental stressors or germline and/or somatic mutations that directly alter the structure of chromatin machinery proteins, their levels, or their regulatory function. These changes can result in an inability of the cell to differentiate along a predefined lineage path, or drive a hyperactive, highly proliferative state with addiction to high levels of transcriptional output. We discuss how these genetic alterations hijack the chromatin machinery for the oncogenic process to reveal unique vulnerabilities and novel targets for cancer therapy.

Figure 1.

Categorization of genetic alterations impacting chromatin in cancer. (SNVs) Single-nucleotide variants, (SEs) superenhancers.

Figure 2.

Chromatin machinery including (A) histone assembly around 147 bp of DNA to form the nucleosome, (B) the DNA modification cycle to methylate cytosine nucleotides, and (C) the variety of chromatin machinery including readers, writers, and erasers of posttranslational marks, DNA-binding transcription factors, chromatin remodeling complexes, and RNA polymerases.

Figure 3.

Fusion oncogenes involving intrinsically disordered chromatin proteins. (A) PONDR score of disorder by amino acid number for EWSR1 and FLI1, with the portions found in Ewing sarcoma fusion oncogene t(11;22)(q24;q12) highlighted in green and blue. (B) PONDR score of disorder by amino acid number for PAX3 and FOXO1, with the portions found in fusion oncogene-positive rhabdomyosarcoma t(2;13)(q35;q14) highlighted in red and brown. (C) PONDR score of disorder by amino acid number for SS18 and SSX1, with the portions fused in t(X;18)(p11.2;q11.2)-positive synovial sarcoma highlighted in orange and purple. (D) Model of BAF dysfunction in synovial sarcoma, where fusion oncogene SS18-SSX disrupts BAF47 incorporation and hinders proper assembly of the complete BAF complex. (Panel D adapted from data in Kadoch and Crabtree 2013.) (E) Violin box plot of mean PONDR scores among plasma membrane proteins, peroxisome proteins, transcription coactivators, transcription factors, PAX fusion partners, and FET RNA-binding proteins. (Panel E adapted from data in Gryder et al. 2020.) (F) Illustration of the cooperation between structured and disordered protein partners commonly found in chromatin-bound oncogenes, and their potential role as contributors to aberrant transcriptional condensates.

Figure 4.

Extrachromosomal DNA includes (A) circularized megabase scale units that include enhancers with abnormal topology and a key oncogene. (B) Examples include extrachromosomal DNAs (ecDNAs) amplified with enhancers for oncogene EGFR in glioblastoma and MYCN in neuroblastoma.