About

Sameer Bajikar is a faculty member associated with the Neuroscience Graduate Program at the University of Virginia. His research specialty focuses on genetics, neurodevelopment, systems biology, and neuroscience. He is involved in exploring the development of the nervous system, neuroimmunology, physiology from channels to circuits, CNS infection, multiple sclerosis, neurodegeneration and injury, and neurodevelopmental disorders. As part of his academic role, he contributes to the training and mentorship of students within the program. His contact email is ssb2v@virginia.edu, and he is connected with the Department of Biology and the Neuroscience Graduate Program at UVA.

Research topics

• Medicine
• Genetics
• Biology
• Cancer research

Selected publications

• Modulating alternative splicing of <i>MECP2</i> is a potential therapeutic strategy for Rett syndrome

  Science Translational Medicine · 2026-03-04 · 3 citations

  articleOpen access

  Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl-CpG–binding protein 2 ( MECP2 ), which encodes a transcriptional regulator essential for maintenance of normal neuronal function. The current US Food and Drug Administration–approved treatment for RTT, trofinetide, mildly alleviates some symptoms. In contrast, reintroducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of MECP2 to switch the less efficiently translated e2 to the more efficiently translated e1 isoform. We deleted Mecp2 exon 2 (unique to e2 ), leading to production of only e1 mRNA, and showed that this up-regulated MeCP2 by 50 to 60% in mice. Next, we investigated the consequences of isoform switching in two independent RTT induced pluripotent stem cell (iPSC)–derived neuron models harboring mutations that reduce both MeCP2 expression and function. Exon 2 deletion in neurons derived from patients with MeCP2-G118E up-regulated MeCP2, ameliorated morphological and electrophysiological changes, and corrected the dysregulated transcriptome in these neurons. Isoform switching in neurons derived from patients with MeCP2-G118E, modeling a severe RTT mutation, only modestly affected MeCP2 protein abundance and, despite this, led to a partial transcriptomic rescue. Last, an exon 2–skipping morpholino up-regulated MeCP2-E1 in vivo in mice. These data set the stage for a potential therapeutic strategy using antisense oligonucleotides to promote isoform switching in patients with RTT who carry partially functioning alleles of MECP2 .

  PublisherDOI

• Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis

  Neuron · 2024-12-16 · 24 citations

  articleOpen access1st authorCorresponding

  Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

  PublisherDOI

• Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression

  Genome Medicine · 2024-12-18 · 16 citations

  articleOpen access

  BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. RESULTS: Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. CONCLUSION: In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.

  PublisherOA PDFDOI

• Modeling antisense oligonucleotide therapy in <i>MECP2</i> duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels

  Human Molecular Genetics · 2024-09-15 · 10 citations

  articleOpen access1st authorCorresponding

  Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.

  PublisherOA PDFDOI

• Quantification of RNAseq and CUT&RUN from MeCP2 adult knockout hippocampus

  Zenodo (CERN European Organization for Nuclear Research) · 2024-12-16

  datasetOpen access1st authorCorresponding
  PublisherDOI

• A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels

  Genes & Development · 2023-10-01 · 15 citations

  articleOpen access

  Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G&gt;A, p.Gly118Glu [G118E]), which has never been seen before in MECP2 , in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.

  PublisherOA PDFDOI

• Quantification of RNAseq and CUT&RUN from MeCP2 adult knockout hippocampus

  Zenodo (CERN European Organization for Nuclear Research) · 2023-12-22

  datasetOpen access1st authorCorresponding
  PublisherDOI

• Author response: MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function

  2023-01-25

  peer-reviewOpen access1st authorCorresponding

  Integrated analysis of transcriptional profiles from mice carrying distinct Mecp2 mutant alleles revealed that MeCP2 regulates Gdf11 expression in the brain, and that Gdf11 is a dosage-sensitive gene whose levels impact neuronal function and animal behavior.

  PublisherDOI

• MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function

  eLife · 2023-02-10 · 13 citations

  articleOpen access1st authorCorresponding

  Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 ( Gdf11 ). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

  PublisherDOI

• Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders

  Proceedings of the National Academy of Sciences · 2022-01-24 · 43 citations

  articleOpen access

  Significance Loss-of-function mutations in MECP2 cause the neurological disorder Rett syndrome (RTT), but the precise molecular mechanism driving pathogenesis remains unclear. Using an unbiased approach to identify proteins that interact with MeCP2, we identified the transcription factor 20 (TCF20) complex and discovered that RTT-causing mutations in MECP2 disrupt this interaction. Using biochemical, morphological, behavioral, and transcriptional studies, we examined the importance of this interaction for brain function and found that the TCF20 complex plays a direct role in MeCP2-dependent gene regulation and modifies MECP2 -induced synaptic and behavioral deficits. Our data uncovered a previously unknown molecular aspect of MeCP2 function and revealed a converging molecular mechanism, whereby mutations of genes encoding several subunits in the same complex contribute to shared neurological symptoms.

  PublisherOA PDFDOI

Recent grants

• Investigating the role of Growth-differentiation factor 11 in neurodevelopmental and MECP2-related disorders

  NIH · $64k · 2019–2021

Frequent coauthors

• Huda Y. Zoghbi

  Baylor College of Medicine

  103 shared

• Zhandong Liu

  Texas Children's Hospital

  72 shared

• Alexander J. Trostle

  Baylor College of Medicine

  57 shared

• Ying‐Wooi Wan

  Baylor College of Medicine

  48 shared

• Yingyao Shao

  Baylor College of Medicine

  45 shared

• Harini P. Tirumala

  Neurological Research Institute

  39 shared

• Jian Zhou

  Shanghai Sixth People's Hospital

  36 shared

• Mark A. Durham

  Baylor College of Medicine

  36 shared

Education

• Doctor of Philospphy, Biomedical Engineering

  University of Virginia

  2016

• Bachelor's of Science, Biomedical Engineering

  University of Virginia

  2010