Research Summary:
We study the mechanisms that govern the specialization and maintenance of nuclear organization across cell types. Summary: 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.
Publications
The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
Lamin B1 and LAP2β resist cytoskeletal force to maintain lamin A/C meshwork organization and preserve nuclear integrity.
Proteome Birthdating: A Single-Sample Approach for Measuring Global Turnover Dynamics and "Protein Age".
C-terminal tagging, transmembrane domain hydrophobicity, and an ER retention motif influence the secretory trafficking of the inner nuclear membrane protein emerin.
What does it take to build a nucleus?
The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
Proteome Birthdating Reveals Age-Selectivity of Protein Ubiquitination.
In vivo protein turnover rates in varying oxygen tensions nominate MYBBP1A as a mediator of the hyperoxia response.
Long lifetime and tissue-specific accumulation of lamin A/C in Hutchinson-Gilford progeria syndrome.
Modeling the consequences of age-linked rDNA hypermethylation with dCas9-directed DNA methylation in human cells.
Intermediate, but not average: The unusual lives of the nuclear lamin proteins.
Long lifetime and selective accumulation of the A-type lamins accounts for the tissue specificity of Hutchinson-Gilford progeria syndrome.
Turnover and replication analysis by isotope labeling (TRAIL) reveals the influence of tissue context on protein and organelle lifetimes.
Moving fast and breaking things: Incidence and repair of DNA damage within ribosomal DNA repeats.
Coaching from the sidelines: the nuclear periphery in genome regulation.
Nucleolar expansion and elevated protein translation in premature aging.
Access of torsinA to the inner nuclear membrane is activity dependent and regulated in the endoplasmic reticulum.
Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics.
Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum.
LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation.
Expression of VACM-1/cul5 mutant in endothelial cells induces MAPK phosphorylation and maspin degradation and converts cells to the angiogenic phenotype.
Estrogen-dependent growth and estrogen receptor (ER)-alpha concentration in T47D breast cancer cells are inhibited by VACM-1, a cul 5 gene.
R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism.
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