Risperidone effects on heterochromatin: the role of kinase signaling

Abstract

Epigenetic effects of anti-psychotic medications are poorly understood. We have appropriated a model whereby heterochromatin is established through 24-or 48-h lipopolysaccharide (LPS) treatment, and tested the epigenetic effects of risperidone along the adenylyl cyclase/protein kinase A (AC/PKA) pathway in human liposarcoma cells that express the LPSsensitive Toll-like receptor (TLR)-4. Human SW872 cells were cultured with LPS and mRNA expression levels and epigenetic modifications of dimethylated lysine 9 of histone 2 (H3K9me2), geterochromatin protein 1γ (HP1γ) and phospho-H3S10 at promoters of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL1β were measured. Pharmacological manipulation of the AC/PKA pathway was achieved through treatment with a PKA inhibitor (H89), mitogen-and stress-activated kinase 1 (MSK1) inhibitor (SB-747651A) or forskolin. Twenty-four and 48-h LPS treatment establishes heterochromatin at selected promoters, corresponding to decreased mRNA expression. Concurrent risperidone treatment with LPS treatment can both 'block' and 'reverse' heterochromatin formation. Forskolin treatment resulted in a similar disassembling effect on heterochromatin. Conversely, inhibition of PKA by H89 or MSK1 both blocked 'normalizing' effects of risperidone on LPS-induced heterochromatin. Our results demonstrate that risperidone can disassemble heterochromatin, exerting this effect along the G-protein/AC/PKA pathway. This approach can also be utilized to investigate functional outcomes of single or combined pharmacological treatments on chromatin assemblies in human cells.

Misexpression of genes lacking CpG islands drives degenerative changes during aging

“…S3 and S4) indicate that these genes are still regulated by heterochromatin despite exhibiting weaker heterochromatin association compared to those in broadly heterochromatin forming CGI − genes (i.e., within cHet domains). This is supported by prior studies demonstrating that local heterochromatin formation within euchromatic domains can suppress expression of surrounding genes [e.g., “local heterochromatin” ( 50 ), “restricted heterochromatin” ( 51 ), or “focal heterochromatin” ( 52 , 53 )] and that up-regulated CGI − genes located within euchromatic domains, such as inflammatory genes Tnf and Il6 , are regulated by heterochromatin formation ( 54 , 55 ). Our counterintuitive observation also explains, at least in part, why heterochromatin decondensation during aging has not been clearly linked with gene expression changes in prior studies ( 56 , 57 ).…”

Differential H3K9me2 heterochromatin levels and concordant mRNA expression in postmortem brain tissue of individuals with schizophrenia, bipolar, and controls

“…Therefore, our non-significant mRNA expression results may be a result of the variable antipsychotic dosing present in our sample. We have also shown that antipsychotic treatment in vitro can decrease heterochromatin levels and increase promoter phosphorylation and mRNA expression of genes that are tolerized (heterochromatinized) via an endotoxin tolerance paradigm, while other promoters do not respond in this way (36,60). This targeted response to antipsychotic treatment could be 10.3389/fpsyt.2022.1006109 an explanation for the LIPJ and NRGN genes that did not show coordination with their H3K9me2 promoter occupation levels.…”

“…Our findings suggest that alternate/parallel signaling pathways capable of targeting genomic heterochromatin may provide a supplemental advantage. Considering this approach, we have elsewhere demonstrated that signaling along the kinase pathways in cell cultures can target heterochromatin assemblies by regulating histone phosphorylation (36). Because heterochromatin is a stable modification and in equilibrium with its regulatory factors, its measurement along specific gene networks in the neuron would allow a reverse engineering approach to study "what stress" deposits heterochromatin on "which network."…”

Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia

“…While CPZE calculated for the participants treated with oral antipsychotics did not differ between illness duration groups, it may be that long-term antipsychotic treatment contributes to shifts in immune signatures in participants with schizophrenia with cumulative effects over the course of illness. Indeed, we have previously shown that antipsychotics can influence the assembly of promoter chromatin and increase immune gene expression (68,69).…”