Embryonic Emergence of Heterochromatin and Nuclear Supervision of Mitochondrial Genetics

异染色质的胚胎出现和线粒体遗传学的核监督

基本信息

项目摘要

Project Summary/Abstract We will address two fundamental aspects of biology in Drosophila. The first involves the mechanisms regulating the onset of differentiation of a naïve embryonic genome. Developmental time resolves progressive steps that introduce the specialized domains of chromatin structure. We found that the molecular hallmarks of heterochromatin emerge late, after heterochromatic behaviors that the marks were thought to specify. We will explore the mechanisms establishing the earlier specializations of heterochromatin domains. Clustered arrays of repeated sequences (satellites) become late replicating in the 14th cell cycle prior to histone methylation (H3K9me) and heterochromatin protein 1 (HP1) binding. We found that regulated recruitment of Rif1, a replication inhibitor, explains developmental onset of late replication, and that a temporal schedule of its dissociation directs a temporal program of sequential replication of the satellites. We will use powerful in vivo tools to understand how time is programmed. But what targets Rif1 to satellite sequences? We found that the satellite sequences are compacted even earlier, prior to Rif1 recruitment, but then what is the basis of compaction? Repetitiveness is the universal distinguishing feature of satellite sequences. Recently, our neighbor Sy Redding and the Rosen lab showed that in vitro assembled chromatin with nucleosomes periodically positioned on repetitive sequences autonomously condenses into a liquid-like phase. In collaboration with Sy Redding we will relate the simple physical observations and in vivo behavior of satellite repeats. The approaches taken here will define the progression of interactions that evolution selected to guide the initial formation of distinct genomic subdivisions that underlie much of complex metazoan biology. The second project examines the genetic independence of the mitochondrial (mt) genome. Despite its bacterial origins, the mt genome is viewed as well adapted; however, an independently transmitted genetic element always has a renegade option. It is cooperative only as long as it is advantageous. The distinct genetics of the multicopied maternally transmitted mt genome is usually learned as uncomplicated, but this is belied by complexities in the transmission of disease mutations and age dependent onset of phenotypes. Inadequate genetic tools have hidden important features of mt genome behaviors that we have accessed with new tools. We show that the ability of a mutant mt genome to compete with the pool of other genomes in a cell determines its fate. The nuclear genome manipulates this inter-mt genome competition to give beneficial outcomes, but fragile points in this nuclear management allow successful transmission of some mutant genomes and underlie an age-associated decline in mt genome integrity. We propose experiments that will dissect the basis of nuclear management of the mt genome. Identifying modulating nuclear activities will enhance predictability of mt disease severity and introduce new avenues for their therapeutic management.
项目总结/文摘

项目成果

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PATRICK H O'FARRELL其他文献

PATRICK H O'FARRELL的其他文献

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{{ truncateString('PATRICK H O'FARRELL', 18)}}的其他基金

Embryonic Emergence of Heterochromatin and Nuclear Supervision of Mitochondrial Genetics
异染色质的胚胎出现和线粒体遗传学的核监督
  • 批准号:
    10619644
  • 财政年份:
    2020
  • 资助金额:
    $ 83.69万
  • 项目类别:
The genetic basis for tissue specific sensitivities to mitochondrial stress
组织对线粒体应激特异性敏感性的遗传基础
  • 批准号:
    8216629
  • 财政年份:
    2011
  • 资助金额:
    $ 83.69万
  • 项目类别:
Host management of the mitochondrial genome
线粒体基因组的宿主管理
  • 批准号:
    9127455
  • 财政年份:
    2011
  • 资助金额:
    $ 83.69万
  • 项目类别:
The genetic basis for tissue specific sensitivities to mitochondrial stress
组织对线粒体应激特异性敏感性的遗传基础
  • 批准号:
    8485607
  • 财政年份:
    2011
  • 资助金额:
    $ 83.69万
  • 项目类别:
The genetic basis for tissue specific sensitivities to mitochondrial stress
组织对线粒体应激特异性敏感性的遗传基础
  • 批准号:
    8334584
  • 财政年份:
    2011
  • 资助金额:
    $ 83.69万
  • 项目类别:
The genetic basis for tissue specific sensitivities to mitochondrial stress
组织对线粒体应激特异性敏感性的遗传基础
  • 批准号:
    8691817
  • 财政年份:
    2011
  • 资助金额:
    $ 83.69万
  • 项目类别:
Nitric Oxide and Responses to Hypoxia in Drosophila
一氧化氮和果蝇对缺氧的反应
  • 批准号:
    7196542
  • 财政年份:
    2000
  • 资助金额:
    $ 83.69万
  • 项目类别:
NITRIC OXIDE AND RESPONSES TO HYPOXIA IN DROSOPHILA
一氧化氮和果蝇对缺氧的反应
  • 批准号:
    6636406
  • 财政年份:
    2000
  • 资助金额:
    $ 83.69万
  • 项目类别:
Nitric Oxide and Responses to Hypoxia in Drosophila
一氧化氮和果蝇对缺氧的反应
  • 批准号:
    6771540
  • 财政年份:
    2000
  • 资助金额:
    $ 83.69万
  • 项目类别:
Nitric Oxide Signaling in Hypoxia and Immunity in Drosophila
果蝇缺氧和免疫中的一氧化氮信号传导
  • 批准号:
    7694365
  • 财政年份:
    2000
  • 资助金额:
    $ 83.69万
  • 项目类别:

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