Biology subjects

Harutyunyan, A. S.

Publications and source records attributed to Harutyunyan, A. S..

3 recordsLinked to original sources

bioRxiv2025

Single-cell sequencing reveals psilocybin induces sustained cell-type specific plasticity in mouse medial prefrontal cortex

Despite enormous interest in psychedelics for psychiatric interventions, potential underlying biological mechanisms remain unclear. Here, we confirm that a single dose of psilocybin increases synaptic transmission in mouse medial prefrontal cortex. Using scRNA-sequencing, we identify cell-type specific mechanisms of sustained neuroplastic effects. We show that, 24h post-psilocybin, expression of plasticity-related genes is increased in excitatory neurons and that transcription in a type of deep layer near projecting neuron, L5/6 NP, is robustly altered. Analyzing receptor expression patterns reveals that this cell-type specificity does not align with 5-HT2A expression but aligns with 5-HT2C expression patterns. Further, multivariate analyses identify psilocybin-induced gene expression patterns in L5/6 NP neurons predict 5-HT2C, but not 5-HT2A, transcript levels. Pharmacologic manipulation with a 5-HT2C antagonist attenuates the post-acute sustained effect of psilocybin on synaptic transmission, highlighting 5-HT2C signaling and L5/6 NP neurons as key mediators of psychedelic drug actions sustained neuroplastic effects in mPFC.

neuroscience↗

bioRxiv2023

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights{square} The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions. {square}The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs. {square}Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture. {square}The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

molecular biology↗

bioRxiv2020

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2

Diffuse midline gliomas and posterior fossa type-A ependymomas contain the highly recurrent histone H3 K27M mutation and the H3 K27M-mimic EZHIP, respectively. In vitro, H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3K27me3 levels, however residual peaks of H3K27me3 remain at CpG islands through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism. Our results highlight the mechanistic similarities between EZHIP and H3 K27M in vivo and provide mechanistic insight for the retention of residual H3K27me3 in tumors driven by these oncogenes.

cancer biology↗