Biology subjects

Hernandez, I. H.

Publications and source records attributed to Hernandez, I. H..

3 recordsLinked to original sources

bioRxiv2024

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis

A major conceptual and clinical challenge in multiple sclerosis (MS) is understanding the mechanisms that drive the central nervous system (CNS)-resident neuroinflammation and neurodegeneration underneath disease progression. Genome-wide association studies (GWAS) have implicated RNA polymerase II (RNAPII) promoter-proximal pausing in oligodendrocyte pathology, but the causal mechanisms remain unclear. Here we find that the C-terminal region of TAF1, a core component of the general transcription factor TFIID, is underdetected in progressive MS brains, which can be explained by endoproteolysis due to extralysosomal cathepsin B (CTSB). Mice lacking the C-terminal TAF1 domain (Taf1d38) exhibit MS-like brain transcriptomic signature, alongside CNS-resident inflammation, progressive demyelination, and motor disability. Mechanistically, C-terminal TAF1 interacts with MS-linked factors that cooperate to regulate RNAPII pausing, particularly affecting oligodendroglial myelination genes. These findings uncover a previously unrecognized transcriptional mechanism underlying MS progression and establish a tractable in vivo model for therapeutic development.

neuroscience↗

bioRxiv2022

Pathogenic mis-splicing of CPEB4 in schizophrenia

Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4{Delta}4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.

neuroscience↗

bioRxiv2020

Huntington's disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

Deregulated alternative splicing has been implicated in a wide range of pathologies. Deep RNA-sequencing has revealed global mis-splicing signatures in multiple human diseases; however, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntingtons disease (HD) pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked effector genes, whose aberrant splicing is associated with decreased protein levels in HD patients and mice. In summary, our intersect-RNA-seq approach unveiled the pathogenic contribution of mis-splicing to HD and could be readily applied to other neurodegenerative diseases for which bona fide animal models are available.

neuroscience↗