Project ID CM-HD2024_62


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Centre for Developmental NeurobiologyWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Centre for Developmental NeurobiologyWebsite

Molecular controls of sex-biased gene expression and disease susceptibility in brain development

X chromosome inactivation (XCI) is an epigenetic mechanism that equalizes X-linked gene dosage between males and females. XCI was believed to persist throughout life, however, certain genes either remain consistently active or become reactivated in a lineage, developmental or ageing-specific manner. The reactivated case of “facultative escapees” is speculated to contribute to female-based disease susceptibility and sexual dimorphisms, but the regulatory mechanisms behind this phenomenon remain unanswered.

Recently, we discovered that several crucial XCI regulators undergo temporal changes in isoform expression during corticogenesis, which may trigger the reactivation of escapee genes. To elucidate an impact of developmentally regulated XCI escapee genes in development and disease susceptibility, this project will take both dry and wet-lab approaches as follow.

1-1: Large-scale profiling of the ENCODE developing RNAseq dataset to capture the developmental and tissue-specific expression of XCI-isoforms.
1-2: in situ validation of the XCI isoform expressions in mouse developing tissues and ES cell differentiation systems.
2-1: CRISPR-based manipulation of XCI isoforms in mouse and human ES/iPS cells
3-1: Investigate the impact of XCI isoforms in ES/iPS-based neuronal differentiation systems
3-2: Large-scale profiling of XCI regulator isoforms in human tissue, cancer and mental disease datasets.

Sahara is a PI focusing on decoding cortical progenitor differentiation processes of in vitro ES/iPS cells as well as mouse as model systems. Our team employs various molecular and biochemical techniques, including CRISPR gene editing and next-generation sequencing, to dissect the molecular pathways behind brain development.

Hamid is a PI in the field of bioinformatics whose lab focuses on understanding post-transcriptional regulation mechanisms underlying the emergence of distinct neuronal cell types. With additional support by a third supervisor, Prof Makeyev, he and his team will support the project by providing strong computational biology expertise and biochemical analysis of RNA biology.

Representative Publications

1. Sahara, S*., Kodama, K., Stevens, CF*. A common rule governing differentiation kinetics of mouse cortical progenitors. PNAS 117, 15221–15229 (2020) * Co-corresponding author 2. Ramos SI, Makeyev EV, Salierno M, Kodama T, Kawakami Y, Sahara S*. Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini. Dev Cell. 2020 Feb 24;52(4):477-491.e8. * Corresponding author 3. Kawaguchi, S., Sahara, S., Zembrzycki, A., and O’Leary, D.D. Generation of Foxg1-IRES-Cre knock-in mice: Circumvention of inconsistent recombination activity and Foxg1 haploinsufficiency in the widely used Foxg1-Cre knock-in mice. (2016) Developmental Biology. pii: S0012-1606(15)30216-5.
1. Hamid, F.*, Alasoo, K., Vilo, J., Makeyev, E.* (2022). Functional Annotation of Custom Transcriptomes. MiMB 2537, 149-172 (2022) *Co-corresponding author 2. Gordon, P.M.*, Hamid, F.*, Makeyev, E.V. et al. A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons. Nat Commun 12, 1918 (2021) *Co-first author 3. Taylor, R., Hamid, F., Fielding, T. et al. Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS. Nat Commun 13, 6994 (2022)