Abigail Buchwalter, Ph.D.


Assistant Professor, Cardiovascular Research Institute

University of California, San Francisco, 10/2018-
Assistant Professor in Residence
Cardiovascular Research Institute
Department of Physiology

The Salk Institute for Biological Studies, 2011-2018
Postdoctoral Fellow with Dr. Martin W. Hetzer
Disruption of the nuclear lamina in premature aging (2014-2018)
Transcription-dependent dynamics of mobile nucleoporins (2011-2014)

Marine Biological Laboratory, 2011
Participant, Physiology Course

Washington University in St. Louis, 2005-2011
Graduate Researcher with Dr. Phyllis I. Hanson
Targeting and activity of the AAA+ ATPase TorsinA within the endoplasmic reticulum
Ph.D. in Biochemistry
Olin Dissertation Award

Hope College, 2001-2005
B.S. in Chemistry with Biochemistry Emphasis
Minor in Mathematics
cum laude

We seek to understand how the organization of the cell nucleus is established, specialized across cell types, and maintained over time to influence cellular identity. “Nuclear organization” involves the non-random packaging of the genome within the nucleus, but also the assembly and interactions of other nuclear structures, such as the nuclear lamina and the nucleolus. 

This work begins with a particular focus on the nuclear lamina, a nuclear structure that is essential for mammalian development and is mutated in ~15 “laminopathy” diseases that afflict the heart, muscle, bone, fat, and nervous system. We focus on three main thematic areas: (i) defining the essential roles that the nuclear lamina plays in nuclear organization, (ii) exploring disruption of nuclear organization as a possible cellular mechanism of aging, and (iii) determining how nuclear organization is maintained or, alternatively, remodeled, over time.

We are honored to be a part of the Cardiovascular Research Institute at UCSF and the Chan Zuckerberg Biohub. We are affiliated with the BMSgraduate program.

 

 

 

 

 

Projects: 
OVERVIEW

The eukaryotic cell nucleus is a densely packed assembly of DNA, RNA, chromatin, and other nuclear bodies, including the nucleolus. How is the nucleus organized, specialized across cell types,  maintained over time, or alternatively, remodeled in response to stimuli? How does this organization affect gene expression and cell function? Our work draws from cell biology, biochemistry, and systems biology to answer these questions.

The protein structures of the nuclear periphery facilitate the non-random organization of nuclear contents, in turn promoting specialization of cell function. The nuclear lamina is a protein meshwork that underlies the nuclear membrane, where it shapes and supports the nucleus. Our work focuses on the roles of the nuclear lamina in establishing and maintaining nuclear organization.

MAINTENANCE OR REMODELING OF NUCLEAR ORGANIZATION

The nuclear lamina scaffolds roughly 30% of the genome and 10% of coding genes in lamin-associated domains (LADs) at the nuclear periphery. LADs are heterochromatic domains that promote cell identity by restricting gene expression.

In higher eukaryotes, the nucleus is entirely disassembled each time a cell divides. However, many cells within functioning tissues have exited the cell cycle. In these cells, how long does nuclear organization endure?

Using metabolic labeling and proteomics in muscle cells, we found that lamin A turns over at a rate similar to many nuclear proteins, while lamin B1 and Lamin B2 are extremely stable.

This implies that a mechanism exists to replace lamin subunits, and that A- and B-type lamin isoforms contribute to nuclear organization on distinct timescales. Future work will define the machinery that turns over lamin A, and determine how manipulating lamin turnover affects nuclear organization and cell function in health and disease.

DEFINING NOVEL ROLES FOR THE LAMINA

We recently found evidence that lamin A regulates the activity of the nucleolus; when cells are either depleted of normal lamin A, or forced to express a mutant form of lamin A that causes progeria, nucleoli expand and become more active. As the site of the energy-intensive process of ribosome biogenesis, nucleoli are exquisitely sensitive to inputs from signaling pathways, and their output shapes cellular metabolism.

This finding suggests a novel function for the lamina that appears to be disrupted in at least one lamin-linked disease. Future work will define how the lamina regulates the nucleolus. We will also explore how nucleolar function changes with developmentally programmed changes in lamin A expression.

DISRUPTION OF NUCLEAR ORGANIZATION DURING AGING

Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by a mutant form of lamin A termed progerin. We discovered that normal lamin A represses nucleoli, and that this repression is lost in progeria. This allows over-production of ribosomes and hyperactive protein synthesis, which depletes cellular energy stores.

We were also able to apply what we learned from progeria to the normal aging process. We found that within human skin cells, nucleoli expand and produce more ribosomal RNA as we age. What drives this? What are the consequences of this on cellular fitness and aging progression? Future work will address these questions.

 

JOIN

WHY JOIN US?

Our mission is to make meaningful contributions to science while fostering an inclusive laboratory culture that values both individual growth and effective teamwork.  We believe that a diversity of perspectives makes for a stronger, more creative team.

GRADUATE STUDENTS

We are accepting rotation students! Email Abby to learn more about potential projects.

POSTDOCTORAL FELLOWS

We are accepting applications from interested postdoctoral fellows. Contact Abby with your CV and a cover letter describing your previous work, future goals, and why you would like to come work with us.

LABORATORY STAFF

We are seeking a staff research associate to join our group – please see this job posting to learn more and apply.

 

Awards: 
Best Postdoctoral Presentation, Salk/UCSD Biology Program Retreat, 2015 Young Investigator Award, Alternative Muscle Club Meeting, 2015 Spencer T. and Ann W. Olin Fellow (Dissertation Award), 2011 Sigma Xi Undergraduate Research Award in Chemistry, 2005 Undergraduate Travel Award, Association for Biochemistry and Molecular Biology Meeting, 2004 Stavros Niarchos Foundation New Frontiers Salk Researcher Specialist Award, 2016 American Society for Cell Biology COMPASS Outreach Grant Award, 2014