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Lawrence C. Myers, PhD

Title(s):
Associate Professor of Medical Education
Associate Professor of Biochemistry and Cell Biology

Department(s):
Medical Education
Biochemistry and Cell Biology

Education:
Harvard University, PHD 1995
Reed College, BA 1990

Programs:
Molecular and Cellular Biology Graduate Programs

Contact Information:

Dartmouth Medical School
HB 7200
Hanover NH 03755


Professional Interests:

Gene Regulatory Mechanisms in Fungal Pathogens that Control Morphological Switches

The ability of a cell to differentiate, or adopt a new identity, and then stably inherit this identity through many rounds of cell division, is critical to all eukaryotic biology. The activation and/or silencing of certain transcriptional programs form the molecular bases for these differences in cell identity. The transcriptional states that are inherited from one cell to another, in the absence of the original signal that led to this state, are defined as epigenetic. These epigenetic switches are involved in processes ranging from the reprogramming of stem cells to X-chromosome inactivation. These epigenetic states also manifest themselves in single-cell organisms as well. Morphological switching (see below) in the fungal pathogen Candida albicans is critical to the basic biology and virulence of the pathogen.

Some C. albicans morphological switches, such as white-opaque switching, are epigenetically regulated. Other switches, such as yeast-hyphal switching, are regulated by a non-epigenetic, but equally fascinating transcriptional mechanism. We study these switches in C. albicans because: some of the more traditional fungal model systems (S. Cerevisiae, S. pombe, etc.) do not strongly exhibit these epigenetic phenomena; and these morphological switches play important role in the virulence of C. albicans and other fungal pathogens. C. albicans presents a substantial infection risk in the clinic with a high mortality that results in tens of thousands of deaths annually in the U.S.. We primarily take a biochemical approach, combined with genetics and genomics, to elucidate the molecular bases of morphological switching and epigenetic gene regulation, and their relation to the virulence of fungal pathogens.


Our current projects are focused on the role of the Mediator complex in these processes. Transcription in purified and extract based systems, in vivo studies, and cell-based assays have revealed Mediator to be a critical functional/physical intermediary between DNA-bound activators and the general transcription factors in all eukaryotes. Mediator has structurally distinct modules referred to as Tail, Middle, Head, and Cdk8. Certain Mediator subunits are critical for the activation of specific sets of genes, while other subunits are essential for transcription of more than 90% of all genes. Work in S. cerevisiae, including our own, has also pointed to a role for Mediator in transcriptional repression and epigenetic silencing that likely involves chromatin. The current projects in utilize our lab's expertise in Mediator to reveal novel mechanistic aspects of the transcriptional morphological switching in C. albicans:

1. White Opaque Switching to Study the Role of Mediator in Epigenetic Silencing. Our recently published (MCB 2011; NAR, 2011; PLoS ONE, 2012) in S. cerevisiae suggests a surprising role for direct interaction between the Mediator complex (traditionally viewed as a co-activator) and chromatin in epigenetic silencing. Based on this work, we predicted that Mediator would be critical in silencing genes that regulated white to opaque switching in C. albicans. Our recent work has validated this hypothesis, and our current work is aimed at discovering the mechanism by which different subunits of Mediator can both positively and negatively regulate certain genes involved in white-opaque switching.

2. The TLO genes of C. albicans work through Mediator. We have purified the Mediator complex from C. albicans and discovered that a single subunit of the 25 subunit complex is encoded by 15 different paralogs (similar genes within the same species), an unprecedented finding among known Mediator subunits. Comparative genomic studies of fungal pathogens had previously indicated that this family of genes (the TLO genes) might be accountable for the potent virulence of C. albicans. Biochemically, we have found that the 'TLO' subunit is anchored to the complex through the Med3 subunit of Mediator (Eukaryotic Cell, 2012). Our genetic studies of the Med3 subunit have shown that its deletion results in a defect in hypha formation (Eukaryotic Cell, 2012) and virulence of the pathogen in a mammalian model of systemic Candidiasis. Our current work is directed at discovering exactly how the TLO genes, Med3 and Mediator participate in regulation of the yeast to hyphal switch and the virulence of the pathogen.


Selected Publications:

 

Role of Mediator in virulence and antifungal drug resistance in pathogenic fungi.
Moran GP, Anderson MZ, Myers LC, Sullivan DJ
Curr Genet. 2019 Jun;65(3):621-630. doi: 10.1007/s00294-019-00932-8. Epub 2019 Jan 14.
PMID: 30637479

Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1.
Liu Z, Rossi JM, Myers LC
Antimicrob Agents Chemother. 2018 Nov;62(11) pii: e00968-18. doi: 10.1128/AAC.00968-18. Epub 2018 Oct 24.
PMID: 30104273

Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance.
Liu Z, Myers LC
Antimicrob Agents Chemother. 2017 Nov;61(11) pii: e01344-17. doi: 10.1128/AAC.01344-17. Epub 2017 Oct 24.
PMID: 28807921

Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans.
Liu Z, Myers LC
Antimicrob Agents Chemother. 2017 Nov;61(11) pii: e01342-17. doi: 10.1128/AAC.01342-17. Epub 2017 Oct 24.
PMID: 28807920

Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp.
Liu Z, Moran GP, Sullivan DJ, MacCallum DM, Myers LC
PLoS Genet. 2016 Oct;12(10):e1006373. doi: 10.1371/journal.pgen.1006373. Epub 2016 Oct 14.
PMID: 27741243

Telomeric ORFS in Candida albicans: does mediator tail wag the yeast?
Sullivan DJ, Berman J, Myers LC, Moran GP
PLoS Pathog. 2015 Feb;11(2):e1004614. doi: 10.1371/journal.ppat.1004614. Epub 2015 Feb 12.
PMID: 25675446

Fungal mediator tail subunits contain classical transcriptional activation domains.
Liu Z, Myers LC
Mol Cell Biol. 2015 Apr;35(8):1363-75. doi: 10.1128/MCB.01508-14. Epub 2015 Feb 2.
PMID: 25645928

Telomeric ORFs (TLOs) in Candida spp. Encode mediator subunits that regulate distinct virulence traits.
Haran J, Boyle H, Hokamp K, Yeomans T, Liu Z, Church M, Fleming AB, Anderson MZ, Berman J, Myers LC, Sullivan DJ, Moran GP
PLoS Genet. 2014 Oct;10(10):e1004658. doi: 10.1371/journal.pgen.1004658. Epub 2014 Oct 30.
PMID: 25356803

Analysis of Candida albicans mutants defective in the Cdk8 module of mediator reveal links between metabolism and biofilm formation.
Lindsay AK, Morales DK, Liu Z, Grahl N, Zhang A, Willger SD, Myers LC, Hogan DA
PLoS Genet. 2014 Oct;10(10):e1004567. doi: 10.1371/journal.pgen.1004567. Epub 2014 Oct 2.
PMID: 25275466

Differential regulation of white-opaque switching by individual subunits of Candida albicans mediator.
Zhang A, Liu Z, Myers LC
Eukaryot Cell. 2013 Sep;12(9):1293-304. doi: 10.1128/EC.00137-13. Epub 2013 Jul 19.
PMID: 23873866

View more publications on PubMed