MeCP2 links heterochromatin condensates and neurodevelopmental disease

Abstract

MeCP2 (methyl CpG binding protein 2) is a key component of constitutive heterochromatin, which plays important roles in chromosome maintenance and transcriptional silencing 1-3 . Mutations in MeCP2 cause Rett syndrome (RTT) [3][4][5] , a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like symptoms that manifests in girls during early childhood. Heterochromatin, long considered a dense and relatively static structure 1,2 , *

Biomolecular Condensates and Cancer

“…Compartmentalization allows for high local concentrations of biomolecules and their substrates and exclusion of other molecules that are not functionally relevant ( Figure 3A) (Gibson et al, 2019;Li et al, 2020). In addition, condensates are nonstoichiometric assemblies of factors involved in shared processes, so, for example, a condensate at the promoter of a gene can assemble multiple RNA polymerase molecules, thereby producing a burst of transcription (Cho et al, 2018;Guo et al, 2019;Kwon et al, 2013;Sabari et al, 2018;Wei et al, 2020).…”

“…Enhancer and promoter elements contain multiple TF binding sites, thus crowding TFs and driving assembly of TFs and coactivators past the threshold for phase separation (Shrinivas et al, 2019). Constitutive heterochromatin condensates form at methylated satellite repeats, due in part to the binding of methylated DNA by MeCP2 and methylated histone H3K9 by HP1 proteins (Larson et al, 2017;Li et al, 2020;Strom et al, 2017). Facultative heterochromatin condensates form at sites of trimethylated H3K27 by virtue of Polycomb-repressive-complex phase separation (Plys et al, 2019;Tatavosian et al, 2019).…”

“…Repressed genes are generally associated with unacetylated nucleosomes, whereas active genes are associated with acetylated nucleosomes (Bradner et al, 2017). Organized into separate subdomains within the nucleus, these two types of chromatin are highly compact yet dynamically accessible to regulation by diverse modifying enzymes and proteins that bind the modified nucleosomes (Larson et al, 2017;Li et al, 2020;Sabari et al, 2018;Strom et al, 2017). Reconstituted unmodified chromatin can undergo liquid-liquid phase separation due to the IDRs of histone tails, producing dense and dynamic droplets.…”

“…The behaviors of proteins involved in chromatin and transcriptional condensates provide instructive examples of selective biomolecular partitioning. Some euchromatic and heterochromatic proteins selectively partition into condensates formed by other components of euchromatin and heterochromatin, and this partitioning behavior may contribute to the separation of these two compartments in the nucleus (Fasciani et al, 2020;Li et al, 2020). Phosphorylation of RNA polymerase II during transcription initiation causes the polymerase to switch between transcriptional and splicing condensates, illustrating how IDR modification can change the partitioning behavior of a macromolecule (Guo et al, 2019;Kwon et al, 2013).…”

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

“…This protein, initially thought to have repressor activity ( Nan et al, 1997 ), is now recognized to have both transcriptionally repressive and activating functions through its interaction with different cofactors ( Yasui et al, 2007 ; Chahrour et al, 2008 ). The protein is able to recognize (or read) DNA and histone methylation marks ( Lewis et al, 1992 ; Thambirajah et al, 2012 ; Lee et al, 2020 ) and, hence, it acts as a methylation-dependent transcriptional modulator within the context of chromatin ( Li et al, 2020 ). DNA methylation dysregulation is one of the hallmarks of diseases such as cancer ( Baylin and Jones, 2016 ), and MeCP2 mutations can alter the reading of this mark, as in RTT ( Kriaucionis and Bird, 2003 ), where it can impact the normal activity of cells.…”