2019 — 2021 |
Yao, Bing |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Roles of Dna Adenine Methylation in Alzheimer's Disease
Alzheimer's disease (AD) is an irreversible, progressive brain disorder featuring gradual decline in memory, language and other areas of cognition. AD is the most common cause of dementia among the elderly worldwide, but no effective treatments are available. Aging has been demonstrated to be the primary risk factor for AD onset. Mounting evidence at the molecular level suggests epigenetic regulation, such as chemical modifications on DNA molecules that modulate special and temporal gene expression, plays fundamental roles in aging progression and AD pathogenesis. Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently found in higher eukaryotic genomes, including mammals. 6mA is dynamically regulated during embryonic development and could play epigenetic roles in regulating gene and transposon expression. However, the molecular functions of 6mA, particularly in the brains, remain largely unexplored. Our preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in Drosophila brains. Consistently, we found a dynamic regulation of 6mA during postnatal mouse brain and human embryoid body development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains, in the loci highly correlated with depression. Importantly, we found global alterations of 6mA and its putative molecular machinery in the brains of human AD patient and an AD mouse model. Our data strongly support 6mA serve as a causal mechanism to contribute to AD pathogenesis. However, there is little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics during aging progression and AD-associated alterations. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (?writers?) and its binding proteins (?readers?) in the mammalian genome limits our understanding of 6mA-dependent epigenetic regulation in normal and diseased brains. Furthermore, the epigenetic roles of 6mA in excitation/inhibition balance of neural circuitries whose perturbation linked to AD pathogenesis remain completely unexplored. Based on these data, we hypothesize that 6mA and its molecular machinery play crucial roles in aging and their dysregulation contribute to AD pathogenesis. We will first delineate 6mA profiling in various brain regions and excitatory/inhibitory neuronal subtypes associated with aging and their dysregulation in AD (Aim 1). We will then define the functions of N6amt1 as a 6mA methyltransferase and determine their roles in aging and AD in excitatory and inhibitory neurons (Aim 2). Our data suggest 6mA could potentially antagonize or recruit hypoxia-induced factor-1 (Hif1) and Drosophila Polycomb (Pc), respectively. Based on these results, we will determine the roles of Hif1 and mammalian Polycomb proteins in aging and AD at the neuronal levels as well (Aim 3). Findings of this study will provide a novel mechanistic insight into disease etiology and are likely to discover new molecular targets with important clinical and translational implications.
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0.966 |
2019 — 2021 |
Yao, Bing |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Roles of Dna Adenine Methylation in Stress Response
Project Summary Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently found in the Drosophila and mammalian genomes. 6mA is dynamically regulated during embryonic development and could play epigenetic roles in regulating gene and transposon expression. However, the roles of 6mA in mammalian brains remain largely unknown. Our preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in Drosophila brains. Preliminary data consistently demonstrated a dynamic regulation of 6mA during postnatal mouse brain and human embryoid body development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains, in the loci highly correlated with depression. The complex changes in postnatal brain development due to the epigenetic alteration could account for the altered stress response and many mental illnesses, the molecular mechanisms connecting these processes remain unclear. The involvement of 6mA and its putative machinery in brain development and stress response makes them an attractive causal mechanism in these connected processes. However, there is little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics and their epigenetic roles during brain development. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (?writers?) and its binding proteins (?readers?) in the mammalian genome hinders our further understanding of their precise epigenetic roles in brain development and stress response. Based on this work, we hypothesize that 6mA and its molecular machinery play crucial roles in mammalian brain development, and their dysregulation contributes to altered stress response in the brain. We will first use established genome-wide 6mA mapping tools to identify brain region-specific and cell type-specific differentially 6mA methylated regions (D6AMRs) during mouse postnatal development and correlate these data with global transcriptome analysis to pinpoint the detailed and precise epigenetic roles of 6mA in these processes (Aim 1). We will then define 6mA putative methyltransferases ?writers? in the mammalian genome and modulate their expression in vivo to test their roles in development-related stress response through 6mA regulation in excitatory and inhibitory neurons (Aim 2). Our data suggest 6mA could potentially antagonize or recruit hypoxia-induced factor-1 (Hif1) and Drosophila Polycomb (Pc), respectively. Based on these results, we will determine the interplay of Hif1 and mammalian Polycomb proteins with 6mA and their roles in development-related stress response at the neuronal levels as well (Aim 3). Findings of this study will provide novel mechanistic insights of 6mA in brain development and its related stress response and are likely to discover new molecular targets with important clinical and translational implications in mental illnesses.
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0.966 |
2019 — 2021 |
Bennett, David Alan (co-PI) [⬀] Bennett, David Alan (co-PI) [⬀] Bennett, David Alan (co-PI) [⬀] Bennett, David Alan (co-PI) [⬀] Yao, Bing Zhao, Jinying [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genome-Wide Mapping and Integrative Analysis of Dna 6ma Methylome in Human Ad Brain
Project Summary Alzheimer?s disease (AD) is the most common form of dementia among older people with no cure or effective treatment. A thorough understanding of its molecular mechanisms is required for discovering novel diagnostic and therapeutic strategies against AD. Chemical modifications of DNA such as methylation play critical roles in regulating gene expression and many other key biological processes, and altered DNA methylation pattern has been implicated in brain aging and AD. While much attention has focused on DNA methylation at the fifth position on cytosine (5mC), recent research identified a new form of DNA modification at the sixth position on adenine (6mA) in mammalian brains. However, little is known about its presence, genomic distribution, and possible functions in human brain and relevance to AD. Our preliminary data in mouse and human brain indicated that 6mA is dynamically responsive to environmental stress and accumulates in human AD brain. Our central hypothesis is that altered signature of 6mA modification is causally associated with AD neuropathology. The objectives of this project are to generate the first detailed map of brain 6mA methylome and identify causative genes harboring aberrant 6mA alterations associated with quantitative neuropathological measures for early features of AD pathology (e.g., amyloid plaques, neurofibrillary tangles). To achieve this, we propose three specific aims: (1) Genome-wide mapping of brain DNA 6mA methylome to identify differentially methylated genes/regions harboring altered 6mA sites (D6AMRs) associated with AD pathology in 1,200 postmortem brain tissue samples collected by two large, community-based population cohorts of aging and dementia. (2) Integrated multiomics analysis to elucidate the potential mechanistic role of 6mA alteration in AD pathology; and (3) Functionally validation of top-ranked candidate genes in 3D brain organoids derived from human iPSCs. This innovative project leverages the wealth of deep clinical and neuropathological phenotypes along with rich omics data including genetic (GWAS, WGS), epigenetic (5mC, 5hmC, 6mA, H3K9Ac), and transcriptome (RNA-seq) profiled on the same prefrontal cortex, and will provide unprecedented opportunities to uncover novel molecular mechanisms implicated in AD pathology. Our proposal brings together an exceptionally strong and unique multidisciplinary team with complementary expertise in genetic epidemiology, statistical genetics, bioinformatics, molecular and neuroepigenetics, and Alzheimer?s research. The work proposed represents the frontier in the interface between AD and omics research. Findings of this study will provide novel mechanistic insight into AD pathogenesis, and are likely to discover new molecular targets with important clinical and translational implications.
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1 |
2019 |
Yao, Bing |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Hypothalamic Manf and Food-Intake Activity
PROJECT SUMMARY Obesity is a major health problem worldwide and also a leading risk factor for various diseases, including type 2 diabetes, stroke, and cardiovascular diseases. Since neuronal activities in the brain are critical for maintaining systemic energy homeostasis, abnormal neuronal functions could lead to the development of obesity; thus, unraveling the complex neuronal mechanisms behind the central control of energy homeostasis is a high priority if we are to understand the biology of obesity and eventually treat or alleviate the health burdens it imposes. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified neurotrophic factor whose protective efficacy has been confirmed in several neurodegenerative diseases, but its endogenous function in the brain remains largely unknown. Recently, we generated a transgenic mouse model in which MANF is overexpressed in the central nervous system. Surprisingly, MANF transgenic mice become obese and exhibit hyperphagia. Moreover, we found endogenous MANF is highly enriched in the hypothalamus, and its expression is closely linked to the feeding status of the mice. These observations led us to hypothesize that MANF is involved in the hypothalamic control of food intake and energy homeostasis. Specific Aims for testing this hypothesis are: Aim (1) To evaluate the phenotypes of mice by increasing or reducing MANF expression in the hypothalamus. We will use virus transduction and CRISPR/Cas9 technology to modulate MANF levels specifically in the hypothalamus and evaluate the metabolic phenotypes of the mice after such modulations; Aim (2) To identify hypothalamic MANF partners in the regulation of energy homeostasis. We will perform affinity purification chromatography followed by tandem mass spectrometry to comprehensively study the MANF interactome in the hypothalamus and how such interactions shape the function of MANF. The results of this study will broaden our knowledge about the neuronal functions that regulate energy homeostasis. Understanding the molecular mechanisms of MANF signaling will yield valuable insights for developing potential MANF-based therapeutic strategies to treat obesity and related neurodegenerative disorders. !
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0.966 |
2021 |
Feng, Yue Yao, Bing |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation and Function of Human Neural Circular Rnas
Project Summary Circular RNAs (circRNAs) are a novel class of covalently closed RNA species derived from ?back splicing? of pre-mRNAs. Mounting evidence suggests the essential roles of circRNAs in governing healthy brain development and their abnormalities in neurological and neuropsychiatric disorders. Many circRNAs are unique and highly abundant in the human brain, which are thought to underlie the sophisticated function of human brains and the fragility of various brain diseases. Mechanistically, circRNAs can function through sponging microRNAs or RNA-binding proteins, which broadly regulate numerous biological pathways. Our current knowledge of molecular mechanisms that regulate circRNA biogenesis in the human brain is still in its infancy. In particular, circRNA biology in human glial cells are poorly understood. Whether neurons and glia cells possess distinct circRNA landscapes and downstream interactomes remain entirely unknown. The biological functions of circRNAs in governing brain development and modulating lesion repair are vastly elusive. These prevailing knowledge gaps limit the current understanding of the complex etiology of many brain diseases. Our long-term goals are to elucidate the regulation and function of circRNAs in healthy and diseased brains, which may help to develop novel therapeutics against brain illnesses. In this application, we focus on circRNA biology in oligodendroglia (OL). OLs are responsible for myelination of the central nervous system and affected in numerous diseases, represented by multiple sclerosis and schizophrenia. Our preliminary data revealed that the RNA-binding protein QKI advances biogenesis of a human OL circRNA, which can promote differentiation of human and rodent OLs. We established state-of-the-art technical platforms to identify circRNA landscapes and interactomes in human OL and neurons. We hypothesize that human circRNAs play essential roles in controlling OL and myelin development, and QKI mediates developmental signals to enhance human OL circRNA biogenesis. In Aim 1, we will determine how QKI regulates OL circRNA biogenesis to advance OL differentiation. In Aim 2, we will determine developmental regulation of human OL circRNA landscapes, downstream pathways, and mechanisms of circRNA action in OLs from multiple platforms with integrated analyses. In Aim 3, we will explore whether human OL circRNA pathways can promote OL lineage development in human induced pluripotent stem cell (iPSC)-derived oligodendrocyte spheres (hOLS) or myelin lesion repair in a well-established mouse model. Findings from these studies will provide novel insights on fundamental rules governing human OL function and myelin repair.
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0.966 |