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Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2024)

Rett Syndrome (RTT) is a neurodevelopmental disorder primarily affecting females, caused by mutations in the MECP2 gene, which encodes the Methyl CpG binding protein (MeCP2). This dissertation explores various facets of MeCP2 function and its role in RTT, integrating findings from multiple studies to provide a comprehensive overview of the current understanding and research gaps.Chapter 1 reviews the known functions of MeCP2, emphasizing its role in transcriptional regulation and the impact of MECP2 mutations on RTT. The chapter summarizes key findings from human cell culture and rodent models, discusses controversies and gaps in the research, and highlights recent discoveries related to potential treatments and therapies. Chapter 2 investigates the effects of Mecp2e1 and MECP2 mutations on gene expression using longitudinal single-nucleus RNA sequencing (snRNA-seq 5’) in a Mecp2e1 mutant mouse model and human postmortem cortices. The study reveals significant sex differences in the number and nature of differentially expressed genes (DEGs), with mutant females showing more pronounced changes prior to symptom onset. These findings contribute to understanding the progression of RTT and the influence of non-cell-autonomous effects on transcriptional homeostasis. Chapter 3 examines the interaction between mutant Mecp2 and environmental factors, specifically persistent organic pollutants (POPs) like PCBs. By exposing wild-type and Mecp2e1 mutant dams to a PCB mixture, the study identifies overlaps in dysregulated genes and pathways between PCB exposure and Mecp2 mutations. This highlights the relevance of environmental factors in RTT pathology. Chapter 4 focuses on transcriptional dysregulation in the hypothalamus of Mecp2e1 mutant mice, using snRNA-seq 5’ to explore cell type-specific and sex-specific variations. The analysis reveals distinct disruptions in synaptic function, cellular metabolism, and neural development, with notable differences between the hypothalamus and cortex. This chapter provides insights into metabolic and neurodevelopmental changes associated with RTT and underscores the importance of considering both cellular and sex-specific factors. Together, these chapters offer a detailed examination of MeCP2’s role in RTT, integrating genetic, environmental, and cellular perspectives to advance the understanding of the disorder and inform future research directions.

    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2021)
    MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.
      Cover page: The Molecular Functions of MeCP2 in Rett Syndrome Pathology
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2024)
      Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo a poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating that wild-type-expressing cells normalize transcriptional homeostasis. These results advance our understanding of RTT progression and treatment.
        Cover page: Sex-specific single cell-level transcriptomic signatures of Rett syndrome disease progression
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2024)
        Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2024)
          Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11 834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
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