Research
Our research focuses on the mechanical properties of the cell nucleus: how the response of the nucleus to force is related to biological characteristics. We study many length scales from molecular responses to force through many cells acting together to resist forces.
Nuclear Structure
The nucleus is made of many complex elements which control genome expression in almost every cell of the body. The regulation of gene expression accounts for temporal and tissue specificity, but the mechanisms are not completely understood. We study the nucleus as a complex mechanical body.
Lamins
The nuclear lamina is a filamentous network of mostly lamin proteins underlying the inner nuclear membrane. Lamins are type V intermediate filament proteins divided in two different types: A-type lamins, which are all products of alternative splicing of the mRNA transduced from the LMNA gene, and B-type lamins, encoded by separate genes. B-type lamins are always expressed in all cell types of metazoans and RNAi gene silencing of LMNB1 and LMNB2 genes drove cells to apoptosis revealing these genes to be essential to cell survival. As such, no genetic diseases involving mutations in genes encoding for lamins arise from mutations in B-type lamins, but many diseases have been identified resulting from mutations in genes encoding for A-type lamins. A-type lamins are differentially expressed at different levels in different tissue types. Further, A-type lamins are not expressed in human embryonic stem cells, and are present only after beginning differentiations. Without A-type lamins, cells are able to survive and proliferate so that they are considered non-essential. Lamin A and lamin C are the most common proteins spliced from lmna. Lamins A and C exchange with the nuclear interior much more than lamin B and are hypothesized to have a greater influence in gene expression at the nuclear interior. A-type lamins also play a major role in the maintenance of nuclear mechanics, structure and shape.
Lamins and DNA
Lamins can interact with chromatin directly via 30-40 nonspecific bp DNA segments and indirectly or via lamin binding proteins. Lamin structures regulate and support protein complexes involved in gene expression; DNA replication, transcription and repair; nuclear positioning; and aging. Loss of or alteration of lamin A through disease is associated with heterochromatin loss at the nuclear periphery and alterations in epigenetic modifications regulating heterochromatin at the nuclear interior. Mechanisms of these lamin-dependent regulations are unknown, but since they are responsible for the structural stability of the nucleus, it is suggested that force may be involved.
Lamins and mechanics
The nuclear lamins are stiff proteins which make up a majority of the nuclear envelope, and lamins are necessary for the structural integrity of the nucleus. Nuclei assembled in lamin-depleted Xenopus egg extracts are highly fragile and nuclei from mouse lmna-null cells are mechanically weak. In vitro rheology of reconstituted lamin B1 solutions shows lamin filaments to be stiff but elastic. Direct mechanical measurements of Xenopus oocyte nuclei also show the in vivo lamina to be a stiff but elastic network.
Lamins and disease
Abnormalities in the lamina due to mutations in lamins and lamin-associated proteins lead to disease pathology, collectively termed laminopathies. There are over 180 known mutations in lamin genes that result in at least 13 different laminopathies. Lamina structure and mechanics play a key role in some of these diseases; increases and decreases in lamin proteins at the nuclear envelope lead to premature aging and muscular dystrophies, respectively. Lamin concentration and organization are also altered in normal aging processes. In most cases, stress-bearing tissues (such as muscle, endothelium, cartilage, etc.) are most affected by nuclear defects, suggesting that alterations in force transmission may be a pathological factor. The underlying mechanisms of these diseases are not well understood, limiting the development of treatments, cures and preventions.