Loss of Setd1b methyltransferase in the murine forebrain as a novel model for human intellectual disability

by Alexandra Michurina
Doctoral thesis
Date of Examination:2020-11-26
Date of issue:2020-12-22
Advisor:Prof. Dr. André Fischer
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Bernd Wollnik
Referee:Prof. Dr. Tiago Fleming Outeiro
Persistent Address: http://dx.doi.org/10.53846/goediss-8380

 

 

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Abstract

English

Methylation of histone 3 lysine 4 (H3K4me3) is an epigenetic mark for active transcription, which is mediated in mammals by six enzymes of the SET1/MLL family of histone methyltransferases (KMTs). All of them have been linked to schizophrenia, neurodevelopmental disorders and intellectual disabilities in humans, but the exact molecular functions of these enzymes in the adult brain remain unclear. In this study we have assessed the consequences of the conditional loss of function of one of the KMTs, the Setd1b histone methyltransferase, from excitatory neurons of the adult murine forebrain. We have evaluated the cognitive abilities of the conditional knock-out (cKO) mice through behavioral tests, analyzed changes in the chromatin landscape and gene expression profiles by neuron-specific ChIP sequencing, RNA sequencing and single cell RNA sequencing. We also made an attempt to restore the severe behavioral phenotype we observed for Setd1b cKO mice with the histone deacetylase inhibitor Vorinostat. In previous studies of our group, we have shown the importance of two other SET1 members for memory consolidation and epigenetic programming, Kmt2a and Kmt2b. However, by comparing all three cKO mice for the respective KMT, we found out that the loss Setd1b impacts neuronal identity genes most significantly and leads to a more drastic impairment of cognitive performance in mice. Our study suggests that Setd1b-related gene-expression programs could be targeted for the treatment of patients suffering from intellectual disabilities.
Keywords: histone methylation; intellectual disability; behavior; RNA-seq; epigenetics
 
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