Scott Kennedy
Associate Professor of Genetics
Ph.D., University of Chicago, 1994-1998
Postdoctoral Research: Massachusetts General Hospital and Harvard University, 1999-2004
Address: 4262 Genetics/Biotech
Telephone: 890-0227
E-mail: sgkennedy@wisc.edu
Research Interests:
Molecular understanding of small RNAs
Research Fields:
C. elegans
Molecular Genetics
Genomics
Research Description:
Epigenetics is the study of changes in gene expression or
phenotypes that are not the result of changes in DNA sequence. For most of the
last century it was widely believed that (unlike genetic information)
epigenetic information did not pass across generational boundaries. In other
words, epigenetic information was erased each and every generation such that
offspring began life with a “blank epigenetic slate”. It is now known that this
is not always true: Many examples of the trans-generational transfer of
epigenetic information have now been documented. The following questions
concerning transgenerational epigenetic inheritance remain unanswered. What is the nature of the signal(s) that directs epigenetic
inheritance? How is epigenetic information maintained across generational
boundaries? Why are some epigenetic signals heritable while others are not? How
often are genes subjected to epigenetic inheritance during the normal course of
reproduction and development, and why? The long-term goal of my research
program is to answer these questions.
To
begin to answer these questions, we have been conducting forward genetic screens in the model organism C. elegans to identify cellular factors
required for multigenerational epigenetic inheritance. To date, these screens
have identified a molecular pathway that couples small interfering RNAs (siRNAs)
to transcriptional gene silencing in nuclei ((termed the nuclear RNAi
defective (Nrde) pathway)). According to our current
model, Argonaute proteins escort siRNAs into nuclei, bind to nascent
transcripts, and recruit the nuclear RNAi factors (NRDE-1/2/4) to genomic sites
of RNAi. Once localized to nascent transcripts, the nuclear RNAi machinery
directs the deposition of repressive chromatin marks (H3K9me3) at RNAi-targeted
loci, and induces silencing of RNA Polymerase II during the elongation phase of
transcription. Together, these nuclear gene-silencing events are responsible
for driving multigenerational RNAi inheritance. A subset of the nuclear RNAi
factors are conserved, hinting that the nuclear RNAi pathway we have identified
in C. elegans may be conserved in all
animals. Finally, we are interested in understanding why animals posses
transgenerational epigenetic inheritance systems. We have found that during the normal course of development,
endogenously expressed small regulatory RNAs direct epigenetic gene silencing
in germ cells. In the absence of the nuclear RNAi machinery, epigenetic
silencing at these genes is lost over generational time. Over a similar
generational time-course, these animals become sterile due to progressively
worsening defects in gamete formation and function. These observations show
that endogenous heritable RNAs
act as specificity factors to promote epigenomic maintenance and immortality of
the germ cell lineage. These data have led us to propose that animals use the
RNAi inheritance machinery (i.e. nuclear RNAi machinery) to transmit epigenetic
information, accrued by past generations, into future generations to regulate
important biological processes.
Representative Publications:
Buckley B, Burkhart K,
Gu SG, Spracklin G,
Kerschner A, Fritz H, Kimble J, Fire A, and Kennedy S, “A nuclear Argonaute promotes multigenerational epigenetic
inheritance and germline immmortality”. Nature. epub: 2012 July 18.
Burton NO, Burkhart KB, Kennedy
S. “Nuclear
RNAi maintains heritable gene silencing in C.
elegans” PNAS. 2011 Dec 6;108(49):19683-8.
Burkhart K,
Guang S, Buckley B, Wong L, Bochner A, and Kennedy
S. “A Pre-mRNA-Associating Factor Links Endogenous siRNAs to Chromatin
Regulation” PLoS Genetics.
2011 Dec 6;108(49):19683-8.
Guang
S, Bochner AF, Burkhart KB, Burton N, Pavelec DM, Kennedy S. “Small Regulatory RNAs inhibit RNA Polymerase II during
the elongation phase of transcription”. Nature. Jun 24;465(7301):1097-101.
(2010).
Pavelec
DM, Lachowiec J, Duchaine TF, Smith HE, Kennedy
S. “Requirement for the ERI/DICER complex in endogenous RNA interference
and sperm development in Caenorhabditis
elegans”. Genetics. Dec;183(4):1283-95. (2009).
Guang,
S., Bochner, A., Pavelec, D., Burkhart, K., Harding, S., Lachowiec, J., Kennedy, S., “An Argonaute transports
siRNAs from the cytoplasm to the nucleus” Science, 321, 537-41
(2008).
Associate Professor of Genetics
Ph.D., University of Chicago, 1994-1998
Postdoctoral Research: Massachusetts General Hospital and Harvard University, 1999-2004
Address: 4262 Genetics/Biotech
Telephone: 890-0227
E-mail: sgkennedy@wisc.edu
Research Interests:
Molecular understanding of small RNAs
Research Fields:
C. elegans
Molecular Genetics
Genomics
Epigenetics is the study of changes in gene expression or phenotypes that are not the result of changes in DNA sequence. For most of the last century it was widely believed that (unlike genetic information) epigenetic information did not pass across generational boundaries. In other words, epigenetic information was erased each and every generation such that offspring began life with a “blank epigenetic slate”. It is now known that this is not always true: Many examples of the trans-generational transfer of epigenetic information have now been documented. The following questions concerning transgenerational epigenetic inheritance remain unanswered. What is the nature of the signal(s) that directs epigenetic inheritance? How is epigenetic information maintained across generational boundaries? Why are some epigenetic signals heritable while others are not? How often are genes subjected to epigenetic inheritance during the normal course of reproduction and development, and why? The long-term goal of my research program is to answer these questions.
To begin to answer these questions, we have been conducting forward genetic screens in the model organism C. elegans to identify cellular factors required for multigenerational epigenetic inheritance. To date, these screens have identified a molecular pathway that couples small interfering RNAs (siRNAs) to transcriptional gene silencing in nuclei ((termed the nuclear RNAi defective (Nrde) pathway)). According to our current model, Argonaute proteins escort siRNAs into nuclei, bind to nascent transcripts, and recruit the nuclear RNAi factors (NRDE-1/2/4) to genomic sites of RNAi. Once localized to nascent transcripts, the nuclear RNAi machinery directs the deposition of repressive chromatin marks (H3K9me3) at RNAi-targeted loci, and induces silencing of RNA Polymerase II during the elongation phase of transcription. Together, these nuclear gene-silencing events are responsible for driving multigenerational RNAi inheritance. A subset of the nuclear RNAi factors are conserved, hinting that the nuclear RNAi pathway we have identified in C. elegans may be conserved in all animals. Finally, we are interested in understanding why animals posses transgenerational epigenetic inheritance systems. We have found that during the normal course of development, endogenously expressed small regulatory RNAs direct epigenetic gene silencing in germ cells. In the absence of the nuclear RNAi machinery, epigenetic silencing at these genes is lost over generational time. Over a similar generational time-course, these animals become sterile due to progressively worsening defects in gamete formation and function. These observations show that endogenous heritable RNAs act as specificity factors to promote epigenomic maintenance and immortality of the germ cell lineage. These data have led us to propose that animals use the RNAi inheritance machinery (i.e. nuclear RNAi machinery) to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.
Buckley B, Burkhart K, Gu SG, Spracklin G, Kerschner A, Fritz H, Kimble J, Fire A, and Kennedy S, “A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immmortality”. Nature. epub: 2012 July 18.
Burton NO, Burkhart KB, Kennedy S. “Nuclear RNAi maintains heritable gene silencing in C. elegans” PNAS. 2011 Dec 6;108(49):19683-8.
Burkhart K, Guang S, Buckley B, Wong L, Bochner A, and Kennedy S. “A Pre-mRNA-Associating Factor Links Endogenous siRNAs to Chromatin Regulation” PLoS Genetics. 2011 Dec 6;108(49):19683-8.
Guang S, Bochner AF, Burkhart KB, Burton N, Pavelec DM, Kennedy S. “Small Regulatory RNAs inhibit RNA Polymerase II during the elongation phase of transcription”. Nature. Jun 24;465(7301):1097-101. (2010).
Pavelec DM, Lachowiec J, Duchaine TF, Smith HE, Kennedy S. “Requirement for the ERI/DICER complex in endogenous RNA interference and sperm development in Caenorhabditis elegans”. Genetics. Dec;183(4):1283-95. (2009).
Guang,
S., Bochner, A., Pavelec, D., Burkhart, K., Harding, S., Lachowiec, J., Kennedy, S., “An Argonaute transports
siRNAs from the cytoplasm to the nucleus” Science, 321, 537-41
(2008).
