James M. Holaska
Research Summary / Selected Publications
My long-term research interests are to elucidate the molecular mechanisms underlying nuclear envelope (NE) regulation of fundamental cellular processes including transcription, chromatin remodeling, cell signaling and DNA replication. We primarily focus on the inner nuclear membrane protein emerin to determine how NE proteins regulate gene expression and nuclear architecture. Mutations in emerin cause Emery-Dreifuss muscular dystrophy (EDMD), which is characterized by progressive skeletal muscle weakening, heart muscle dysfunction, life-threatening irregular heart rhythms and contractures of major tendons.
Regulation of Lmo7 transcription activity by emerin: Implications for EDMD
Lmo7 is a transcription activator of muscle and cardiac genes, including emerin. Lmo7 directly binds myogenic genes and activates myogenic differentiation. We hypothesize that Lmo7 is an EDMD-relevant transcription regulator because Lmo7-null mice have dystrophic muscles and emerin directly regulates Lmo7 activity. To begin understanding the functional interaction between Lmo7 and emerin, and how Lmo7 regulates tissue-specific gene expression crucial for muscle differentiation, we are characterizing the domain structure of Lmo7, analyzing the molecular mechanisms of Lmo7-dependent transcription, and investigating the regulation of myogenic differentiation by emerin and Lmo7.
Emerin and chromatin remodeling
Generally, expressed genes are contained within regions of decondensed chromatin structures called euchromatin. Repressed genes tend to reside in regions of compacted chromatin called heterochromatin, which is often juxtaposed to the NE. Since emerin interacts with chromatin-repressive machinery, we hypothesize that emerin actively represses chromatin at the NE. My lab is actively testing this hypothesis by studying formation of emerin-containing chromatin remodeling complexes at the NE and regulation of chromatin remodeling complex formation and heterochromatin regulation by emerin.
My long-term research interests are to elucidate the molecular mechanisms underlying nuclear envelope (NE) regulation of fundamental cellular processes including transcription, chromatin remodeling, cell signaling and DNA replication. We primarily focus on the inner nuclear membrane protein emerin to determine how NE proteins regulate gene expression and nuclear architecture. Mutations in emerin cause Emery-Dreifuss muscular dystrophy (EDMD), which is characterized by progressive skeletal muscle weakening, heart muscle dysfunction, life-threatening irregular heart rhythms and contractures of major tendons.
Regulation of Lmo7 transcription activity by emerin: Implications for EDMD
Lmo7 is a transcription activator of muscle and cardiac genes, including emerin. Lmo7 directly binds myogenic genes and activates myogenic differentiation. We hypothesize that Lmo7 is an EDMD-relevant transcription regulator because Lmo7-null mice have dystrophic muscles and emerin directly regulates Lmo7 activity. To begin understanding the functional interaction between Lmo7 and emerin, and how Lmo7 regulates tissue-specific gene expression crucial for muscle differentiation, we are characterizing the domain structure of Lmo7, analyzing the molecular mechanisms of Lmo7-dependent transcription, and investigating the regulation of myogenic differentiation...
Holaska, JM and Wilson KL. 2007. An emerin proteome: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling and nuclear architecture. Biochemistry 46, 8897-8908.
Holaska, JM and Wilson KL. 2006. Lmo7, an emerin-binding protein that shuttles between the cell surface and nucleus and regulates emerin transcription. Hum Mol Genet. 15, 3459-3472.
Holaska JM, Lee KK, Kowalski AK, and Wilson KL. 2003. Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro. J Biol Chem. 278, 6969-75.
Holaska JM, Kowalski AK, and Wilson KL. 2004. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear envelope. PloS Biol, 2, 1354-1362.
Haraguchi T, Holaska JM, Yamane M, Koujin T, Hashiguchi N, Mori C, Wilson KL, and Hiraoka Y. 2004. Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy. Eur J Cell Biol 271, 1035-1045.
Mislow JM, Holaska JM, Kim MS, Lee KK, Segura-Totten M, Wilson KL, McNally EM. 2002.
Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro. FEBS Lett 525, 135-40.
Holaska, JM and Wilson KL. 2007. An emerin proteome: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling and nuclear architecture. Biochemistry 46, 8897-8908.
Holaska, JM and Wilson KL. 2006. Lmo7, an emerin-binding protein that shuttles between the cell surface and nucleus and regulates emerin transcription. Hum Mol Genet. 15, 3459-3472.
Holaska JM, Lee KK, Kowalski AK, and Wilson KL. 2003. Transcriptional repressor germ cell-less (GCL) and barrier to autointegration factor (BAF) compete for binding to emerin in vitro. J Biol Chem. 278, 6969-75.
Holaska JM, Kowalski AK, and Wilson KL. 2004. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear envelope. PloS Biol, 2, 1354-1362.
Haraguchi T, Holaska JM, Yamane M, Koujin T, Hashiguchi N, Mori C, Wilson KL, and Hiraoka Y. 2004. Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy. Eur J Cell Biol 271, 1035-1045.
