The central role of chromatin regulators in brain development and function
The ability of stem cells to self-renew and produce multiple daughter cell lineages requires the expression of certain sets of genes, repression of other loci, and transcriptional “plasticity” of many others.
In normal development, such genome-wide transcriptional programs are in part regulated by chromatin structure – the “packaged” state of DNA with histone proteins.
Genomic studies of neurodevelopmental and psychiatric disorders have revealed mutations in many chromatin regulators. Furthermore, chromatin regulators are frequently mutated or aberrantly expressed in brain tumors.
Chromatin regulators play key roles in the identity of neural stem cells (left) and production of specific cell types (right).
Interplay of trithorax and Polycomb group chromatin regulators in neural stem cells
The trithorax and Polycomb group factors are part of an evolutionarily conserved cellular “memory” system that specify cell identity by regulating chromatin. Trithorax factor MLL1 is required for neurogenesis from neural stem cells (NSCs) in the adult mouse brain (Lim et al., Nature, 2009). Without MLL1, key neurogenic genes have high levels of histone-3 lysine-27 trimethylation (H3K27me3), a chromatin modification related to transcriptional repression.
EZH2 – a Polycomb factor that catalyzes H3K27me3 – is not downregulated during neurogenesis (Hwang et al, eLIFE, 2014), suggesting that removal of H3K27me3 is required for expression of neurogenic genes. The H3K27-specific demethylase JMJD3 is required for neurogenesis, de-repressing specific promoters and enhancers of neurogenic genes, and MLL1 is required for the local recruitment of JMJD3 (Park, Cell Rep et al., 2014).
Understanding the interactions between MLL1, JMJD3, and EZH2 are current mechanistic research aims.
A new model for how neural stem cells "remember" their identity
After ventral NSC identity is established by the morphogen SHH, this positional information is "handed off" to MLL1
The brain develops from NSCs that have distinct regional identities, and defects in the positional information of NSCs result in abnormal brain development. Mutations in MLL1 cause Wiedemann-Steiner syndrome, a disorder that includes developmental delay and autism. We've found that MLL1 maintains NSC regional identity during embryonic brain growth (Delgado, Manskey, et al., Science 2020).
The mechanisms that enable the “scaling” of developmental patterns during tissue growth are poorly understood. Given that the human brain grows to a very large size, the mechanisms of scaling are especially important to our understanding of human neurodevelopmental disorders.
Some ongoing research...
- Neurodevelopmental function and molecular mechanism(s) of JMJD3 (KDM6B).
- Targeting chromatin-modifying activities to specific genes with CRISPR-Cas9 fusions.
- Molecular mechanisms of MLL1 in neural stem cells.
- Can manipulation of chromatin regulator activity in neural stem cells improve their clinical utility?
