Role of lysine demethylase 5c in neurodevelopment and intellectual disability
Year: 2018
Type: dissertation
Abstract: Numerous neurodevelopmental syndromes are caused by mutations in chromatinmodifying\n\t\t\t\t enzymes. One of such enzymes, the lysine demethylase 5C (KDM5C) is\n\t\t\t\t mutated in Claes-Jensen X-linked intellectual disability (CJ-XLID), a\n\t\t\t\t neurodevelopmental disorder associated with intellectual problems and adaptive\n\t\t\t\t behaviour impairment. KDM5C demethylates histone H3 di- or trimethylated at lysine 4\n\t\t\t\t (H3K4me2/3), two histone modifications associated with active transcription. In this\n\t\t\t\t thesis, I used murine and cellular models of the disease to gain deeper insight into the\n\t\t\t\t genomic actions of this protein and its differential role in the developing and adult\n\t\t\t\t brain. We compared the behaviour, transcriptome and epigenomic landscapes of Kdm5c\n\t\t\t\t null (KO) and forebrain-restricted inducible knockout (ifKO) mice. KOs showed strong\n\t\t\t\t neurological phenotypes mimicking patients’ symptoms such as decreased learning and\n\t\t\t\t memory, epileptic seizure propensity and altered emotions. In contrast, ifKOs only presented some spatial learning deficits, suggesting a predominant developmental\n\t\t\t\t component in KDM5C-associated ID. Furthermore, consistent with the proposed\n\t\t\t\t general function for Kdm5c as a transcriptional repressor, both KO and ifKO mice\n\t\t\t\t showed excessive hippocampal transcription and histone H3K4 tri-methylation at\n\t\t\t\t promoters and enhancers. In particular, exclusively KO mice showed (i) neuronal\n\t\t\t\t expression of germ line genes that escaped developmental silencing by DNA\n\t\t\t\t methylation, and (ii) over-activation of activity-regulated enhancers involved in\n\t\t\t\t cognitive processes, such as those at the Npas4, Arc and Fos loci. Although the\n\t\t\t\t importance of these functions declines after neuronal maturation, Kdm5c still retains a\n\t\t\t\t genome surveillance role preventing the illegitimate activation of non-neuronal and\n\t\t\t\t cryptic promoters in adult neurons. Finally, to characterize how a disease-associated mutation affects early stages of human brain development, I produced the first cerebral\n\t\t\t\t organoids derived from induced pluripotent stem cells (iPSCs) of CJ-XLID patients.
Author: Marilyn Scandaglia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2808640701