Genome Folding and Regulation in Diploid Multicellular Organisms

项目概要/摘要 功能性多细胞生物体由从单个细胞产生的各种细胞类型组成。这个迷人 这一过程涉及时空基因活动和基因组组织的变化。中断 染色体相互作用和基因表达可导致发育障碍或癌症。尽管 尽管在多尺度基因组结构和基因调控方面出现了引人注目的新观点，但我们的知识仍然非常有限。 限制了母本和父本基因组如何容纳在每个细胞中以实现不同的细胞分化。 身份此外，仍然不清楚父母之间的结构杂合性如何影响 基因组结构和功能，使细胞状态从正常变为功能失调。挑战的区别 同源染色体之间，特别是在单细胞分辨率，阻碍了我们的能力， 关于亲本基因组的变异性和异质性以及相关功能意义的紧迫问题。 我们以前的工作涉及互补方法的发展，包括单倍型特异性组学 和变革性的单细胞成像来区分同源物。我们的目标是利用这些强大的 确定二倍体基因组的包装和功能调节如何形成的方法， 维持，以及基因组完整性被破坏如何影响细胞命运。具体来说，我们将确定父母如何 贡献影响复杂的早期基因组包装和调控。此外，我们将研究可塑性 在组织内建立和维持单细胞身份。最后，我们将揭示如何 包括转座子在内的亲本内容中的杂合性影响基因组的完整性，从而增加我们的遗传多样性。 了解亲本基因组相容性和生物体活力。这些研究将 为我们对亲本染色体折叠的基本理解提供了一个增强的框架， 调节以更好地解释功能失调的染色体对疾病的贡献。

PROJECT SUMMARY / ABSTRACT A functional multicellular organism consists of various cell types that arise from a single cell. This fascinating process involves changes in spatio-temporal gene activity and genome organization. Disruptions in chromosomal interactions and gene expression can lead to developmental disorders or cancer. Despite the remarkable emerging views on multi-scale genome architecture and gene regulation, our knowledge is still very limited on how maternal and paternal genomes are accommodated in each cell to achieve diverse cellular identities. Moreover, it remains poorly understood how structural heterozygosity between parents may impact genome structure and function to tip over cell state from normal to dysfunctional. Challenges in distinction between homologous chromosomes, especially at single cell resolution, have hampered our ability to ask pressing questions about variability and heterogeneity of parental genomes and related functional significance. Our previous work involved the development of complementary approaches including haplotype-specific omics and transformative single-cell imaging to distinguish homologs. Our goal is to leverage these powerful approaches to determine how packaging and functional regulation of diploid genomes are formed and maintained, and how disrupted genome integrity affects cell fate. Specifically, we will determine how parental contribution influences intricate early genome packing and regulation. Furthermore, we will investigate plasticity in establishment and maintenance of single-cell identities within tissues. Finally, we will uncover how heterozygosity in parental content including transposons affects genome integrity, and thereby increase our understanding of parental genome compatibility and organismal viability. Together, these proposed studies will provide an enhanced framework for our foundational understanding of parental chromosome folding and regulation to better interpret contribution of dysfunctional chromosomes to disease.