Biology subjects

Lardner, C. K.

Publications and source records attributed to Lardner, C. K..

2 recordsLinked to original sources

bioRxiv2023

Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region. Stress induction of H3K27me1 was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which is induced by chronic stress and controls H3K27 methylation patterns. Overexpression of the VEFS domain led to social, emotional, and cognitive abnormalities, and altered excitability of NAc D1 mediums spiny neurons. Together, we describe a novel function of H3K27me1 in brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.

neuroscience↗

bioRxiv2022

Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

The ability of neurons to respond to external stimuli involves adaptations of gene expression. The transcription factor, {Delta}FOSB, is important for the development of drug addiction, however, its gene targets have not been identified. Here we use CUT&RUN to map the genome-wide enrichment of {Delta}FOSB binding in the two major neuronal cell types of the nucleus accumbens, a key brain reward region, after cocaine exposure. The binding landscape shows that the majority of {Delta}FOSB peaks occur outside of promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with {Delta}FOSB peaks, consistent with earlier studies of {Delta}FOSBs interacting proteins. In addition, in silico analyses predict that {Delta}FOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of {Delta}FOSBs molecular mechanisms in transcriptional regulation.

neuroscience↗