Probing heterochromatin growth and memory dynamics in live single cells

生物体的每个细胞都包含相同的遗传信息，然而发展独特的细胞类型要求在任何给定的细胞中只有部分信息是可访问的。这种选择性访问是由细胞核内的结构控制的，这些结构沿着大段染色体组装，根据细胞类型生长到不同的程度，然后抑制潜在的信息。如果每次细胞分裂都重复这一过程，这种抑制是可遗传的。目前尚不清楚这些被称为异染色质的结构是如何(I)沿着染色体生长，以及(Ii)在细胞分裂过程中“记住”它们的组装和生长位置。本研究项目旨在解决这些问题，从而为构建或操纵遗传信息控制异染色质结构以驱动细胞采用新的命运和执行新的功能奠定基础。该项目还将通过研究培训和教学机会，在不同的科学领域培养不同的本科生和研究生，包括遗传学、生物物理学、细胞生物学和生物技术。虽然异染色质抑制基因沉默的遗传要求已经研究很久了，但控制细胞中异染色质沿染色体生长(扩散)的规则仍然不清楚。也不知道为什么某些异染色质元件在细胞分裂过程中保持表观遗传，而其他异染色质元件不能。在本项目中，我们利用单细胞分裂酵母模型系统来研究异染色质的传播和维持机制。这项研究将把在单个分裂酵母细胞中实时可视化和量化扩散的能力与朗之万动力学模型结合起来，以区分异染色质如何在细胞周期内沿着染色体扩散的不同模型。为了了解通过传播形成的异染色质是如何在细胞分裂中被记忆的，含有异染色质扩散报告的分裂酵母细胞的滞后测量将被用来评估在给定的异染色质区域内的记忆程度。酵母遗传学、单细胞成像和建模相结合的力量有望对表观遗传记忆的分子起源产生新的见解。这项研究由生物科学局分子和细胞生物科学部的遗传机制计划资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Each cell of an organism contains the same genetic information, yet development of unique cell types requires that only part of this information be accessible in any given cell. This selective access is governed by structures inside the cell nucleus that assemble along large stretches of a chromosome, grow to variable extents depending on the cell type and then repress the underlying information. If this process is repeated every cell division, this repression is heritable. It remains unclear how these structures, known as heterochromatin, (i) grow along the chromosome, and (ii) “remember” their sites of assembly and growth over cell divisions. This research project aims to resolve these questions, and thereby help lay the foundation to build or manipulate genetic information-controlling heterochromatin structures to drive cells to adopt new fates and perform new functions. The project will also educate diverse undergraduate and graduate students in different scientific fields, including genetics, biophysics, cell biology, and biotechnology, through research training and teaching opportunities. While the genetic requirements for gene silencing by heterochromatin have been long studied, the rules governing heterochromatin growth (spreading) along the chromosome in cells remain opaque. Neither it is understood why certain heterochromatin elements epigenetically maintain themselves across cell divisions while others do not. In this project, the single-celled fission yeast model system is employed to investigate the mechanisms of spreading and maintenance of heterochromatin. The research will combine the ability to visualize and quantify spreading in real-time in single fission yeast cells with Langevin dynamics modeling to distinguish different models of how heterochromatin spreads along the chromosome within the cell cycle. To understand how heterochromatin formed by spreading is remembered across cell divisions, hysteresis measurements with fission yeast cells containing heterochromatin spreading reporters will be used to assess the degree of memory within a given heterochromatin domain. The power of yeast genetics, single cell imaging and modeling combined is expected to yield new insights into the molecular origins of epigenetic memory.This research is funded by the Genetic Mechanisms program in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.