# Single amino-acid differences define H2B variants and modify chromatin accessibility to induce EMT in breast cancer

## TL;DR

This paper shows that specific H2B histone variants, like H2B1O, are linked to worse breast cancer outcomes and can drive cancer progression by altering chromatin structure and promoting EMT.

## Contribution

The study identifies H2B1O as a novel onco-histone variant associated with breast cancer subtype-specific dysregulation and chemotherapy resistance.

## Key findings

- H2B1O overexpression is more common in certain breast cancer subtypes and populations, correlating with worse prognosis.
- H2B1O compacts nucleosome structure and activates pro-inflammatory and oncogenic pathways, inducing EMT and chemotherapy resistance.
- H2B variant expression is proposed as a prognostic biomarker and potential therapeutic target in breast cancer.

## Abstract

Histones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes. HIST1H2BO overexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis. In vitro studies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy.