Joslin Investigator Details

A Harvard Medical School Affiliate

Welcome to the Joslin Research Website


	Joslin Investigator:

Investigator Specifics:

Professional Details:

CV not available

Member of Section:

Current Fellows, Students, or Lab Members:

Riva Garvin, Ph.D.

Kira Glover-Cutter, Ph.D.

Jess Porter

Stacey Robida, M.Sc.

Jennifer Tullet, Ph.D.

Jinling Wang, Ph.D.

Past Fellows, etc.:

Jae Hyung An, Ph.D.

Arzu Atalay, Ph.D.

Rosanna Baker

Peter Boag, Ph.D.

Jiayun Lu, Ph.D.

Michael Lucke

Elizabeth Veal

Kelly Vranas

Amy Walker

Investigators

Adjunct Investigators

Fellows & Team Members

DERC Cores

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Joslin Resources

T. Keith Blackwell, M.D., Ph.D.

Associate Professor of Pathology

Harvard Medical School

Section Head: Developmental & Stem Cell Biology

Joslin Diabetes Center

Senior Investigator

Joslin Diabetes Center

1/1/2004 -

Our lab is pursuing a group of related projects addressing issues in gene regulation, and cell differentiation and function. Most of our work involves the model organism C. elegans.

More research information can be found at the Blackwell Lab Website

SKN-1 and oxidative stress resistance

The C. elegans transcription factor SKN-1 specifies formation of the feeding and digestive system (mesendoderm) during early embryogenesis. We have found that during larval and adult stages SKN-1 is required for resistance to oxidative stress. Now we are investigating how SKN-1 activates its embryonic and post-embryonic target genes, and how its localization and activity are regulated in response to oxidative and metabolic stresses. C. elegans provides a powerful genetic system for studying oxidative stress resistance pathways that are important in disease states that include diabetes, atherosclerosis and HIV, and possibly for longevity and cancer prevention.

Papers:
An JH, Vranas K, Lucke M, Inoue H, Hisamoto N, Matsumoto K, Blackwell TK. (2005) Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci USA, 102, 16275-16280.

Inoue H, Hisamoto N, An JH, Oliveira RP, Nishida E, Blackwell TK, Matsumoto K. (2005) The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev., 19, 2278-2283.

An JH, Blackwell TK. (2003) SKN-1 links C. elegans mesendodermal specifications to a conserved oxidative stress response. Genes Dev., 17, 1882-1893.

Walker AK, See R, Batchelder C, Kophengnavong T, Gronniger JT, Shi Y, Blackwell TK. (2000) A conserved transcription motif suggesting functional parallels between C. elegans SKN-1 and Cap ‘n’ Collar-related proteins. J. Biol. Chem., 275, 22166-22171.

Kophengnavong T, Carroll AS, Blackwell TK. (1999) The SKN-1 amino terminal arm is a DNA specificity segment. Mol. Cell. Biol., 19, 3039-3050.

Carroll AS, Gilbert DE, Liu X, Cheung JW, Michnowicz JE, Wagner G, Ellenberger TE, Blackwell TK. (1997) SKN-1 domain folding and basic region monomer stabilization upon DNA binding. Genes Dev. 11, 2227-2238.

Blackwell TK, Bowerman B, Priess J, Weintraub H. (1994) Formation of a monomeric DNA binding domain by Skn-1 bZIP and homeodomain elements. Science, 266, 621-628.

Germ cell and embryonic gene regulation

We have determined that the C. elegans embryo is a powerful system for studying transcription regulation in vivo because initially it relies on maternally-derived mRNA, and can tolerate RNAi-depletion of even essential transcription factors. With this system we can investigate in a metazoan how general transcription machinery components contribute to regulation of different gene classes. We have found that while some components of the initiation factor TFIID are dispensible for transcription of developmental and other metazoan-specific genes, TAF-4 appears to be required for essentially all early embryonic transcription. We have also determined that the elongation factor and kinase P-TEFb is required for in vivo phosphorylation of the RNA Polymerase II C-terminal domain repeat on serine 2, an event associated with elongation, and for essentially all transcription. At heat shock genes P-TEFb is needed primarily to counteract inhibition by the elongation factor SPT-4/SPT-5, but at other genes it has additional functions. We will expand these in vivo transcription studies to include genetic, microarray, structure-function, and mechanistic analyses. The lab is also interested in understanding specialized gene regulation mechanisms that operate in the C. elegans germline, a model stem cell population. In the early embryo germline transcription is silenced by PIE-1, a predicted RNA-binding zinc finger protein. We have shown that PIE-1 is a direct transcriptional repressor, and are investigating this activity.

Papers:
Boag PR, Nakamura A, Blackwell TK. (2005) A conserved RNA-protein complex component involved in physiological germline apoptosis regulation in C. elegans. Development, 132, 4975-4986.

Navarro RE, Blackwell TK. (2005) Requirement for P granules and meiosis for accumulation of the germline RNA helicase CGH-1. Genesis, 42, 172-180.

Wang JC, Walker A, Blackwell TK, Yamamoto KR. (2004) The Caenorhabditis elegans ortholog of TRAP240, CeTRAP240/let-19, selectively modulates gene expression and is essential for embryogenesis. J. Biol. Chem., 279, 29270-29277.

Walker AK, Shi Y, Blackwell TK. (2004) An extensive requirement for transcription factor IID-specific TAF-1 in Caenorhabditis elegans embryonic transcription. J. Biol. Chem., 279, 15339-15347.

Takagi T, Walker AK, Sawa C, Diehn F, Takase Y, Blackwell TK, Buratowski S. (2003) The Caenorhabditis elegans mRNA 5'-capping enzyme. In vitro and in vivo characterization. J. Biol. Chem., 278, 14174-14184.

Zhang F, Barboric M, Blackwell TK, Peterlin BM. (2003) A model of repression: CTD analogs and PIE-1 inhibit transcriptional elongation by P-TEFb. Genes Dev., 17, 748-758.

Walker AK, Blackwell TK. (2003) A broad but restricted requirement for TAF-5 (hTAFII100) for embryonic transcription in C. elegans. J. Biol. Chem., 278, 6181-6186.

Shim EY, Walker AK, Blackwell TK. (2002) Broad requirement for the Mediator subunit RGR-1 for transcription in the C. elegans embryo. J. Biol. Chem., 277, 30413-30416.

Shim EY, Walker AK, Shi Y, Blackwell TK. (2002) CDK-9/Cyclin T (P-TEFb) is required in two post-initiation pathways for transcription in the C. elegans embryo. Genes Dev., 16, 2135-2146.

Walker AK, Rothman JH, Shi Y, Blackwell TK. (2001) Distinct requirements for C. elegans TAFIIs in embryonic transcription. EMBO Journal, 20, 5269-5279.

Navarro RE, Shim EY, Kohara Y, Singson A, Blackwell TK. (2001) cgh-1, a conserved predicted RNA helicase required for gametogenesis and protection from physiological germline apoptosis in C. elegans. Development, 128, 3221-3232.

Batchelder C, Dunn, MA, Choy B, Suh Y, Cassie C, Shim EY, Shin TH, Mello C, Seydoux, G, Blackwell TK. (1999) Transcriptional repression by the Caenorhabditis elegans germline protein PIE-1. Genes Dev. 13, 202-212.

More research information can be found at the Blackwell Lab Website