Pancreatic cancer remains at a stagnant 5-year survival of <13%, attributed to the high heterogeneity and plasticity of these tumors. To circumvent this, we focus on the abundant nuclear protein high mobility group-box protein 2 (HMGB2). HMGB2 depletion is key for establishing replicative senescence in normal cells, but it is significantly overexpressed across multiple cancer types. Here, we combine single-cell and spatial genomics with patient-derived organoids and tumor samples to show how increased HMGB2 availability represents a transcriptional addiction that fuels cell-cycle progression and growth. We repurpose a small molecule inhibitor targeting HMGB2 to interfere with its binding to DNA, restrict chromatin accessibility at promoters, and constrain tumor growth both in vitro and in vivo. 3D chromatin interactions involving HMGB2-bound enhancers and promoters also collapse upon drug treatment. Thus, pharmacological HMGB2 targeting represents a universal strategy for managing cancer progression irrespective of its genetic or molecular characteristics.
Adi Danieli-Mackay, Ioanna Papadionysiou, Markos Tsitsianopoulos et al.· Cell Reports· 0 citations
N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes and is essential for Arabidopsis embryogenesis. However, how m6A mRNA methylation is coordinated with other regulatory pathways during development including embryogenesis remains largely unknown. Here, we report the SWI/SNF chromatin-remodeling subunit SWI3B as a bona fide interactor of the m6A methyltransferase MTA. Like m6A writer mutants, SWI3B is required for early embryo development. We demonstrate that the interaction between MTA and SWI3B is required for MTA function during embryogenesis. MTA and SWI3B are both required to establish the correct expression pattern of WOX8 and proper auxin maxima during early embryogenesis. Transcriptome analysis of isolated embryos from mta, swi3b, and fip37 mutants identified a shared set of upregulated transcripts, including STM as well as several NAC and ERF transcription factors that are normally absent or expressed at very low levels during early embryogenesis. Embryo-specific overexpression of ANAC087 and ERF114 genes phenocopied early embryonic defects observed in mta and swi3b mutants, indicating that their ectopic expression contributes to the observed developmental phenotype. Moreover, SWI3B and MTA are both required for m6A deposition on specific developmental transcripts. Together, our findings uncover a mechanism by which chromatin remodeling and m6A-mediated RNA regulation cooperate to suppress the precocious stability of key developmental regulators, thereby contributing to the establishment of the transcriptional program required for early embryo patterning in Arabidopsis. Highlights The SWI/SNF subunit SWI3B is a functional interactor of the m6A methyltransferase MTA during Arabidopsis embryogenesis SWI3B and MTA cooperate to establish embryo patterning, WOX8 expression, and auxin maxima MTA and SWI3B suppress precocious expression of STM, ANAC087 and ERF114 transcription factors that disrupt early embryo development SWI3B links chromatin-associated regulation with m6A-mediated control of transcript stability Graphical abstract
Wen Gong, U. Schwartz, L. Fu et al.· bioRxiv· 0 citations