Biology subjects

Lachance, C.

Publications and source records attributed to Lachance, C..

3 recordsLinked to original sources

bioRxiv2026

Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma

Low-grade endometrial stromal sarcoma (LGESS) exhibits frequent chromosomal translocations that fuse various subunits of the NuA4/TIP60 co-activator complex to subunits of the Polycomb Repressive Complex 2 (PRC2) complex. LGESS fusion proteins, such as the commonly occurring JAZF1-SUZ12, have been shown to upregulate genes through mislocalization of NuA4/TIP60 activity to Polycomb target genes. In this study, we characterized an interesting recurrent fusion protein in LGESS that fused a NuA4/TIP60 component, MBTD1, to EZHIP. EZHIP is a recently described vertebrate protein that enzymatically inhibits methyltransferase activity of the PRC2 complex and is a potent oncogene. The MBTD1-EZHIP fusion protein forms a chimeric TIP60-PRC2.1 complex and drastically reduces H3K27me3 levels at Polycomb target genes, similar to EZHIP-overexpressing cancers. However, unlike EZHIP overexpression, MBTD1-EZHIP requires mislocalization of NuA4/TIP60 activity through the MBTD1 protein to upregulate oncogenes. Despite differences in the finer molecular mechanisms, MBTD1-EZHIP and the common JAZF1-SUZ12 fusion protein upregulated similar sets of genes in cell lines, showing a convergence of oncogenic gene expression. Surprisingly, unlike in cellular models, JAZF1-SUZ12 translocated patient samples showed not only upregulation of genes driven by increased H4K8ac and decreased H3K27me3 but also downregulation of specific genes due to accumulated H3K27me3, revealing an additional oncogenic mechanism in LGESS.

cancer biology↗

bioRxiv2025

Concomitant acetylation and loading of H2A.Z by NuA4/TIP60 regulate target gene transcription

The human NuA4/TIP60 complex is a multi-subunit, dual enzymatic epigenetic factor and gene regulator. It bears histone acetyltransferase (HAT) activity towards the canonical histones H2A and H4 and the histone variant H2A.Z, a function that has been linked to gene activation. It also acts as a chromatin remodeling enzyme through ATP-dependent exchange of nucleosomal H2A-H2B dimers with H2A.Z-H2B, leading to incorporation of H2A.Z into chromatin at gene regulatory elements. NuA4/TIP60 is unique in merging two enzymatic activities targeting H2A.Z. Both NuA4/TIP60-dependent H2A.Z acetylation and remodeling have been linked to several physiological functions and pathologies, but studies have only focused on either one or the other enzymatic activity, and insights on functional coordination between them are lacking. Here, we leverage our EP400 rapid depletion system to explore and untangle the intricate links between H2A.Z acetylation by Tip60 (the HAT subunit) and loading on chromatin by EP400 (the remodeling subunit) through functional genomic and biochemical analyses. Our data support a mechanism in which H2A.Z is first pre-acetylated to allow for H2A.Zac-H2B dimer association with the complex before incorporation into chromatin, particularly at gene promoters to positively regulate transcription. As both H2A.Z-targeted enzymatic functions of NuA4/TIP60 have been linked to disease, albeit separately, our findings hold important implications for therapeutic intervention, where combinatorial targeting is a promising avenue.

molecular biology↗

bioRxiv2019

NuA4-dependent H4 acetylation is adopted to specifically control photosynthesis-related genes

NuA4, an essential histone acetyltransferase complex, is required for efficient transcription in eukaryotes. Using genome editing, genomic approaches and biochemical assays, we characterized plant homologues of two key components of this complex, EPL1 and EAF1 in Arabidopsis thaliana. Surprisingly, we found that loss of AtEPL1, which is necessary for enzymatic activity of NuA4, is not lethal. Contrary to yeast, mutants lacking AtEAF1, responsible for complex targeting, display severe pleiotropic phenotype which copies that of Atepl1. Atepl1 and Ateaf1 mutants grow slowly, contain reduced chlorophyll levels and small chloroplasts. We provide evidence that these alterations are not caused by disturbance of GLK transcription factors, the major regulators of chloroplast development. Using ChIP-seq we show that H4 acetylation levels are dramatically reduced in the chromatin of the Atepl1 mutant, while H3 acetylation remains mostly unchanged. We use our data to define NuA4-dependent genes and show that chloroplast-related genes are significantly overrepresented in this group, consistent with the pale-green phenotypes of the mutants. We propose that NuA4 was adopted in plants to control nuclear-encoded photosynthesis genes. SignificancePhotosynthesis depends on chloroplast proteins, most of which are nucleus-encoded and thus subject to control mechanisms common across eukaryotes. Here we show that NuA4, an evolutionary conserved transcriptional coactivator, is necessary for proper development of photosynthetic apparatus. Surprisingly, in contrast to yeast and metazoans, plants engineered to lack core NuA4 subunits are capable of vegetative development despite dramatic genome-wide loss of NuA4-dependent H4K5 acetylation. This chromatin perturbation seems to directly affect 350 genes which, in addition to reduced H4K5ac levels, display decreased transcript levels but no loss of transcription-related H3K9ac. A significant proportion of these genes are related to chloroplast function, particularly to translation, an intriguing parallel to the yeast NuA4s role in transcription of ribosome biogenesis-related genes.

molecular biology↗