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，但独特细胞类型的发育只需要在任何给定细胞中获得部分信息。这种选择性的进入是由细胞核内的结构控制的，这些结构沿着沿着大的染色体延伸，根据细胞类型生长到不同的程度，然后抑制潜在的信息。如果这个过程在每一次细胞分裂中都重复，那么这种抑制是可遗传的。目前还不清楚这些被称为异染色质的结构是如何（i）沿着染色体沿着生长的，以及（ii）在细胞分裂过程中“记住”它们的组装和生长位点的。该研究项目旨在解决这些问题，从而为构建或操纵控制遗传信息的异染色质结构以驱动细胞采用新的命运并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，教育不同科学领域的不同本科生和研究生，包括遗传学，生物物理学，细胞生物学和生物技术。虽然异染色质沉默基因的遗传要求已经研究了很长时间，但异染色质在细胞中沿着染色体沿着生长（扩散）的规则仍然不清楚。也不理解为什么某些异染色质元件在细胞分裂中表观遗传地保持自己，而另一些则不。本项目采用单细胞分裂酵母模型系统来研究异染色质的扩散和维持机制。该研究将结合联合收割机的能力，以可视化和量化传播实时在单分裂酵母细胞与朗之万动力学建模，以区分异染色质如何传播的不同模型沿着染色体在细胞周期内。为了理解通过铺展形成的异染色质如何在细胞分裂中被记忆，将使用含有异染色质铺展报告基因的裂殖酵母细胞的滞后测量来评估给定异染色质结构域内的记忆程度。酵母遗传学的力量，单细胞成像和建模相结合，预计将为表观遗传记忆的分子起源提供新的见解。这项研究由生物科学理事会分子和细胞生物科学部的遗传机制项目资助。该奖项反映了NSF的法定使命，并通过利用基金会的智力价值和更广泛的评估被认为值得支持影响审查标准。

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.