Defining molecular and gene-regulatory dysregulation in Down Syndrome tissues and models

定义唐氏综合症组织和模型中的分子和基因调节失调

基本信息

项目摘要

PROJECT ABSTRACT Down syndrome (DS) is a neurodevelopmental disorder causing cognitive deficits including impaired learning and memory, and language development, affecting 1 in 750 newborns. DS is caused by triplication of chromosome 21 (T21), leading to altered gene dosage, and to changes in the proportion of brain cell types, and in neuronal morphology and maturation, suggesting a neurodevelopmental etiology. However, the underlying molecular mechanisms causing the observed neuropathology and functional deficits are still largely unknown. Progress has been hindered by the overall complexity of brain architecture, an incomplete knowledge of the cell types and molecular pathways dysregulated in DS during development, and limited human-relevant experimental models. Moreover, bulk transcriptome and epigenome profiling indicates that T21 not only alters gene dosage within the locus, but also leads to broad changes in gene expression and may lead to altered gene regulatory dynamics. Based on these data, we hypothesize that increased chr21 gene dosage alters global gene expression in neural progenitors, changing neural cell fate specification and differentiation. Here, we leverage novel genomic technologies including joint single-nucleus transcriptome (snRNAseq), single-nucleus chromatin accessibility (snATACseq) profiling, and single-cell joint chromatin interaction and methylation profiling (sc-m3C-seq), as well as primary human neural progenitors (phNPCs), a validated model of human corticogenesis, to test this hypothesis. We will first define cell-specific molecular and gene-regulatory dysregulation in DS by performing joint snRNAseq, snATACseq and sc-m3C-seq in a collection of control and DS developing neocortex, at a time period of peak neurogenesis. This comprehensive multi-omic profiling will uncover changes in cell composition and cell-specific gene expression signatures in DS neocortex as well as reveal perturbations in cellular lineage maps and specification. By integrating single-cell expression and epigenetic profiles we will define the proximal and distal gene regulatory elements, as well as the transcription factors driving DS disease mechanisms. Finally, we will leverage a unique collection of DS patient-derived and control phNPC lines to model disease in vitro in order to characterize neural progenitor proliferation and specification in DS, as well as changes in neuronal morphogenesis and synaptogenesis. We perform joint snRNAseq and snATACseq over a differentiation timeline that recapitulates embryonic to mid-gestation corticogenesis in order to interrogate cellular, molecular and gene regulatory dysregulation in DS and directly compare this model with in vivo DS mechanisms. Altogether, we present a comprehensive project providing an in-depth cell biological and molecular characterization of DS progression using in vivo tissues and a human-relevant model, and establishes this model for future mechanistic interrogation. The long-term goal of this research is to provide the foundational molecular knowledge that will ultimately contribute to the development of treatments for DS.
项目摘要

项目成果

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Luis de la Torre-Ubieta其他文献

Luis de la Torre-Ubieta的其他文献

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{{ truncateString('Luis de la Torre-Ubieta', 18)}}的其他基金

Defining molecular and gene-regulatory dysregulation in Down Syndrome tissues and models
定义唐氏综合症组织和模型中的分子和基因调节失调
  • 批准号:
    10588168
  • 财政年份:
    2022
  • 资助金额:
    $ 19.44万
  • 项目类别:
Defining gene regulatory networks driving cortical evolution and brain development
定义驱动皮质进化和大脑发育的基因调控网络
  • 批准号:
    10616776
  • 财政年份:
    2021
  • 资助金额:
    $ 19.44万
  • 项目类别:
Defining gene regulatory networks driving cortical evolution and brain development
定义驱动皮质进化和大脑发育的基因调控网络
  • 批准号:
    10440238
  • 财政年份:
    2021
  • 资助金额:
    $ 19.44万
  • 项目类别:
Defining gene regulatory networks driving cortical evolution and brain development
定义驱动皮质进化和大脑发育的基因调控网络
  • 批准号:
    10039955
  • 财政年份:
    2021
  • 资助金额:
    $ 19.44万
  • 项目类别:

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