Laura Mathies, Ph.D.
Department: Department of Pharmacology and Toxicology
Phone: (804) 828-8397
Molecular Medicine Research Building, Room 3038
1220 East Broad Street
Stanford University, 1996
SWI/SNF chromatin remodeling in the acute alcohol response
Allelic variation in members of the SWI/SNF chromatin-remodeling protein complex has been associated with a diagnosis of alcohol dependence in humans. We have found that altering the function of the SWI/SNF complex in C. elegans alters acute behavioral responses to ethanol. My research is aimed at uncovering the mechanisms by which this complex controls ethanol responses, and, because the SWI/SNF complex regulates transcription, to determine the downstream genes that mediate these effects. C. elegans is an excellent model for these studies, because there is strong conservation between the machinery of nervous system function in humans and worms, and there are excellent genetic resources available to experimentally manipulate nervous system function in C. elegans. The goals of this project are: 1) to determine the specific neurons and neural circuits in which the SWI/SNF complex is required for acute ethanol responses and 2) to identify genes that are regulated by the SWI/SNF complex in differentiated neurons. With this information in hand, we will use genetic and behavioral analysis to identify the genes that are responsible for the acute behavioral response to ethanol and determine the biological mechanisms by which they regulate ethanol responses.
SWI/SNF chromatin remodeling in multipotency
Adult stem and progenitor cells are multipotent, meaning that they are capable of dividing to produce a few related cell types. My research uses progenitors of the C. elegans reproductive system as a model for defining the genes and molecular mechanisms that regulate and determine this capacity. The somatic gonadal progenitors (SGPs) are multipotent progenitors that generate all somatic tissues of the reproductive system. Each SGP is the product of a cell division that produces one SGP and one differentiated cell, the head mesodermal cell (hmc). Therefore, in this single cell division, the potential to generate all of the somatic gonadal types is differentially segregated into one daughter cell. We have found that components of the C. elegans SWI/SNF complex are required to distinguish SGPs from their differentiated hmc sisters. Molecularly distinct SWI/SNF complexes are expressed in pluripotent stem cells, multipotent progenitors, and differentiated cells, suggesting that different SWI/SNF complexes are likely to play important roles in each of these different cell states. We are using a combination of fluorescence activated cell sorting (FACS) and RNA sequencing to identify genes that distinguish multipotent SGPs from their differentiated hmc sisters, and to learn the mechanisms by which SWI/SNF chromatin remodeling complexes regulate these cell fates.
Mathies LD, Lindsay JH, Handal AP, Blackwell GG, Davies AG, Bettinger JC (2020). SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol. BMC Genomics 21(1):646.
Schmitt RE, Shell BC, Lee KM, Shelton KL, Mathies LD, Edwards AC, Grotewiel M (2019). Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity. Alcohol Clin Exp Res. 43(9):1872-1886.
Lee KM, Mathies LD, Grotewiel M (2019). Alcohol sedation in adult Drosophila is regulated by Cysteine proteinase-1 in cortex glia. Commun Biol. 3;2:252.
Mathies LD, Ray S, Lopez-Alvillar K, Arbeitman MN, Davies AG, Bettinger JC (2019). mRNA profiling reveals significant transcriptional differences between a multipotent progenitor and its differentiated sister. BMC Genomics 28;20(1):427.
Mathies LD, Aliev F; COGA Investigators, Davies AG, Dick DM, Bettinger JC (2017). Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations. Alcohol Clin Exp Res. 41(12):2033-2040.
Mathies LD, Blackwell GG, Austin MK, Edwards AC, Riley BP, Davies AG, Bettinger JC (2015). SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans. PNAS 10;112(10):3032-7.
Raabe RC, Mathies LD, Davies AG, Bettinger JC (2014) The omega-3 fatty acid eicosapentaenoic acid is required for normal alcohol response behaviors in C. elegans. PLoS One 9:e105999.
Large EE and Mathies LD (2014). Caenorhabditis elegans SWI/SNF subunits control sequential developmental stages in the somatic gonad. G3 4(3): 471-483.