Transcriptional Regulators in the Cerebellum in Chronic Schizophrenia: Novel Possible Targets for Pharmacological Interventions

TL;DR

This study identifies key transcription factors in the cerebellum of people with chronic schizophrenia that may control multiple altered proteins and biological processes.

Contribution

The study provides a novel panel of transcriptional regulators in the cerebellum that could serve as pharmacological targets in schizophrenia.

Findings

Eleven enriched transcription factors were identified, including SP1, YY1, and EGR1, which control 250 altered proteins in the cerebellum of individuals with chronic schizophrenia.

SP1, KLF7, and SP4 from the Krüppel superfamily had the largest number of target proteins.

Transcription factor targets were enriched in pathways related to transport, signaling, inflammation, and RNA processing, suggesting their broad regulatory roles.

Abstract

Despite the emerging evidence of the role of transcriptional regulators in schizophrenia as key molecular effectors responsible for the dysregulation of multiple biological processes, limited information is available for brain areas that control higher cognitive functions, such as the cerebellum. To identify transcription factors that could control a wide panel of altered proteins in the cerebellar cortex in schizophrenia, we analyzed a dataset obtained using one-shot liquid chromatography–tandem mass spectrometry on the postmortem human cerebellar cortex in chronic schizophrenia (PXD024937 identifier in the ProteomeXchange repository). Our analysis revealed a panel of 11 enriched transcription factors (SP1, KLF7, SP4, EGR1, HNF4A, CTCF, GABPA, NRF1, NFYA, YY1, and MEF2A) that could be controlling 250 altered proteins. The top three significantly enriched transcription factors were SP1, YY1, and EGR1, and the transcription factors with the largest number of targets were SP1, KLF7, and SP4 which belong to the Krüppel superfamily. An enrichment in vesicle-mediated transport was found for SP1, KLF7, EGR1, HNF4A, CTCF, and MEF2A targets, while pathways related to signaling, inflammation/immune responses, apoptosis, and energy were found for SP1 and KLF7 targets. EGR1 targets were enriched in RNA processing, and GABPA and YY1 targets were mainly involved in organelle organization and assembly. This study provides a reduced panel of transcriptional regulators that could impact multiple pathways through the control of a number of targets in the cerebellum in chronic schizophrenia. These findings suggest that this panel of transcription factors could represent key targets for pharmacological interventions in schizophrenia.

Figures