Rett syndrome (RTT) is a postnatal progressive neurodevelopmental disorder associated with severe mental disability and autism-like syndromes that manifests in girls during early childhood, and is caused by mutation of the X-linked DNA binding protein MeCP2 (Methyl CpG-binding Protein 2). Mice carrying null alleles of Mecp2 closely mimic symptoms seen in patients and are faithful models of the disease. Importantly, development of RTT-like symptoms can be slowed or even halted in the adult following correction of a mutant Mecp2 allele by transgene-mediated MeCP2 expression. MeCP2 is one of the most abundant proteins in neurons, and most disease-causing mutations cluster in the DNA binding domain (MBD) and in the transcription repression domain (TRD). However, the function of MeCP2 remains enigmatic, with two major hypotheses having been proposed: (i) MeCP2 acts as repressor of transcription or (ii) as an activator of transcription. Clearly, none of these proposed functions can fully explain the complex phenotype of MeCP2 deficiency or overexpression leading to RTT or MECP2 Duplication Syndrome. Based on our preliminary evidence we postulate that MeCP2?s primary function may be to modulate the 3D chromosome architecture through condensate formation. Components of both euchromatin and heterochromatin can form phase-separated condensates, which provide a mechanism to compartmentalize and concentrate biochemical reactions within cells and are produced by liquid-liquid phase separation driven by intrinsically disordered regions (IDRs) of proteins. MeCP2 protein contains a large IDR and we have obtained preliminary evidence that MeCP2 is involved in phase- separated heterochromatin condensates. Thus, beyond MeCP2?s role as a repressor or activator of gene expression, the protein may have a much wider and more complex role in the cell physiology and disease. In this project we will define the contribution of MeCP2 to heterochromatic and euchromatic condensates in normal and mutant neurons and analyze the effect of RTT causing mutations on LLPS. Our goal is to gain insights into the function of MeCP2 as the basis for designing novel therapeutic approaches. Potential new therapies based on this hypothesis will take time to develop into applications. To explore a more immediate approach we will use epigenetic editing as a therapeutic tool to activate the inactive wt MECP2 allele located on the inactive X chromosome. Most importantly, epigenetic editing will restore MeCP2 expression to exactly wild type levels and thus avoid toxic consequences of MeCP2 overexpression. In contrast, other strategies such as using vector-mediated MeCP2 transduction will invariably produce cells that overexpress MeCP2 and thus will result in serious side effects as seen in patients with MECP2 duplication syndrome.

Public Health Relevance

Rett syndrome (RTT), caused by mutation of the DNA binding protein MeCP2, is one of the most common causes for mental retardation in females, with promising but limited therapeutic results in clinical trials to halt disease progression. The physiological function of the protein in neurons is complex and not well understood, hampering efforts to devise more effective therapeutic strategies. Using human ES cells, epigenetic editing and mouse transgenic approaches, this project establishes the function of MeCP2 in transcriptional condensates as a basis for novel therapeutic approaches.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Roessler, Reinhard; Goldmann, Johanna; Shivalila, Chikdu et al. (2018) JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons. Life Sci Alliance 1:e201800094
Ma, Haiting; Wert, Katherine J; Shvartsman, Dmitry et al. (2018) Establishment of human pluripotent stem cell-derived pancreatic ?-like cells in the mouse pancreas. Proc Natl Acad Sci U S A 115:3924-3929
Cohen, Malkiel A; Markoulaki, Styliani; Jaenisch, Rudolf (2018) Matched Developmental Timing of Donor Cells with the Host Is Crucial for Chimera Formation. Stem Cell Reports 10:1445-1452
Mellios, N; Feldman, D A; Sheridan, S D et al. (2018) MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry 23:1051-1065
Sahakyan, Anna; Kim, Rachel; Chronis, Constantinos et al. (2017) Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation. Cell Stem Cell 20:87-101
Weintraub, Abraham S; Li, Charles H; Zamudio, Alicia V et al. (2017) YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell 171:1573-1588.e28
Soldner, Frank; Stelzer, Yonatan; Shivalila, Chikdu S et al. (2016) Parkinson-associated risk variant in distal enhancer of ?-synuclein modulates target gene expression. Nature 533:95-9
Hockemeyer, Dirk; Jaenisch, Rudolf (2016) Induced Pluripotent Stem Cells Meet Genome Editing. Cell Stem Cell 18:573-86
Banerjee, Abhishek; Rikhye, Rajeev V; Breton-Provencher, Vincent et al. (2016) Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc Natl Acad Sci U S A 113:E7287-E7296
Ji, Xiong; Dadon, Daniel B; Powell, Benjamin E et al. (2016) 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell 18:262-75

Showing the most recent 10 out of 16 publications