Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder

Abstract

135 words): RNA-sequencing analyses are often limited to identifying lowest p-value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA-sequencing of human male-and female-originated cell lines, and connectomics of transcription factor-and microRNA-interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. While these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method explicates the differences between afflicted men and women, and identifies diseaseaffected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function, interlinked by microRNAs. This approach may open new perspectives for seeking biomarkers and therapeutic targets, also in other transmitter systems and diseases.Manuscript (Erta et al., 2012): the gp130 co-receptor (also known as IL6ST, IL-6 signal transducer), and the LIF-receptor. Gp130-family neurokines unite properties of neurotrophic (e.g. on dopaminergic neurons) and immunogenic nature, both prominent facets in the molecular etiology of SCZ and BD (Harrison, 2015) and in cholinergic signaling (Stanke et al., 2006). Neurokines can activate JAK1/2, TYK2 and STAT1/3/5A/5B (Rawlings, 2004), affecting neurotransmission as well as immunity. However, to the best of our knowledge, their roles in SCZ/BD were not yet studied.SCZ/BD hallmarks also involve circadian perturbations. The cholinergic-catecholaminergic imbalance in BD (Van Enkhuizen et al., 2015) follows variable transcriptionally-regulated rhythms (e.g. CLOCK, ARNTL, RORA), and affected individuals exhibit decreased REM latency (the duration from onset of sleep to the first rapid eye movement phase) and increased vulnerability for disease that can be modulated by muscarinic agonists/antagonists (Ising et al., 2005). Correspondingly, the muscarinic M1/M3 receptor genes are essential for REM sleep (Niwa et al., 2018), and sleep deprivation exerts short-term antidepressant effects (Wu and Bunney, 1990), reduced cortical ACh levels (Boonstra et al., 2007), and vast transcriptional changes in basal forebrain cholinergic neurons (Nikonova et al., 2017).The quantitative measurement of disease-relevance of individual perturbed genes is a common methodological problem in transcriptomic analyses. To reduce complexity, transcripts are often filtered by their p-values, leading to bias towards few highly expressed and differentially regulated genes. This does not agree with a polygenic model where each component contributes a small effect. To alleviate this bias while still attempting the necessary complexity reduction, we developed an integrative approach of multiple perspectives. Jerusalem and Andreas Meisel, Berlin and to Dr. Ester Bennett, Jerusalem ...

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…Thanks to these studies, an overview of differences in rodents is slowly building up allowing comparisons with evidence from psychiatric patients to be made. These high‐throughput studies include both microarray and RNA‐sequencing approaches. Both types of technologies allow for a genome‐wide profiling of stress responses in the two sexes and the study of these responses in the context of pathways.…”

Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex, and Parkinson's disease‐related changes

“…To examine the potential activity of tRFs as regulators of gene expression, we chose to focus on the cholinergic system, which tends to be impaired with age (Perry, 1980), and in neurodegenerative diseases such as PD (Bohnen & Albin, 2011). For this purpose, we defined Cholino‐tRFs as tRFs with the potential to target one core cholinergic gene (i.e., one of the enzymes responsible for the synthesis or breakdown of acetylcholine; cholinergic gene list acquired from Lobentanzer et al, 2019) or at least five genes associated with cholinergic activity in a similar manner to microRNAs (Figure 5a; prediction done by sequences complementarity between the tRFs and the targets, see Methods).…”

“…Regarding AD, ample evidence reports sncRNAs shedding into the CSF of patients with AD. A number of miRs, such as miR‐222 and the acetylcholinesterase‐targeting miR‐125b (Lobentanzer et al, 2019), have been shown to be DE in the CSF of AD patients (Dangla‐Valls et al, 2017). Finally, DE sncRNAs have also been shown in the CSF of PD patients, where hsa‐mir‐626, for example, has been the main focus—both as a potential biomarker for disease severity and as a potential therapeutic target (Xia et al, 2019).…”

“…Targets with prediction score <0.8 were dropped, aiming to keep only the most plausible targets of each tRF. The specific potential of cholinergic targets was assessed based on predicted targeting of 94 genes that have been associated with cholinergic activity in the brain (Lobentanzer et al, 2019). The genes were weighted by their direct influence on the cholinergic system (Table S1; annotations created using Ensembl release 106—Apr 2022 © EMBL‐EBI; Cunningham et al, 2022) and the cholinergic targeting potential of each tRF was set as the sum of the weight of all of its predicted cholinergic targets.…”

MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases

“…Although miR-125b and miR-29b are the top-ranked AD biomarkers in several clinical studies [129][130][131], the mechanism of dysregulation in the blood of AD patients is still unclear. In silico analysis reveals that miR-125b regulates the cholinergic neuron functions by targeting Clock [132]. Further, recent evidence shows that miR-125b regulates neuronal cell growth and apoptosis via the regulation of inflammatory factors and oxidative stress, and this regulation may be related to AD pathogenesis [133].…”