Header Logo
Last Name

Amy K Walker PhD

TitleAssociate Professor
InstitutionUniversity of Massachusetts Medical School
DepartmentProgram in Molecular Medicine
AddressUniversity of Massachusetts Medical School
373 Plantation Street, Two Biotech, Suite 308
Worcester MA 01605
vCardDownload vCard
    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentProgram in Molecular Medicine

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    Collapse ORNG Applications 
    Collapse Websites

    Collapse Biography 
    Collapse education and training
    Auburn University, Auburn, AL, United StatesBSMicrobiology
    State University of New York, Stony Brook, Stony Brook, NY, United StatesPHDMolecular Microbiology

    Collapse Overview 
    Collapse overview

    How is transcriptional regulation of lipogenesis linked to diet and environment in C. elegans and mammals

    SREBP (sterol regulatory element binding protein) transcription factors activate genes important for cholesterol metabolism, fatty acid (FA) and synthesis of phospholipids, in addition to ensuring production of additional important co-factors. We have found unexplored regulatory links between lipid metabolism and the one-carbon cycle (1CC), discovering that SREBP proteins in C. elegans and mammals control expression of 1CC genes. The 1CC provides methyl groups for PL biosynthesis and epigenetic regulation; regulation by SREBPs provides a novel layer of nutrition-dependent input to methylation-dependent processes. Alterations in 1C metabolism and SREBP function are associated with similar diseases, suggesting that co-regulation with lipid homeostasis may be a common impact point in metabolic-associated disorders such as obesity and fatty liver disease.

    Most methylation reactions require SAMe (s-adenosyl methionine). Conversion of methionine to SAMe by MAT1A/MAT2A in humans, or the SAMS proteins in C. elegans, affects cellular processes from phosphatidylcholine (PC) biosynthesis to protein or DNA modification. We have found that SREBPs regulate sams-1 and MAT1A expression in both C. elegans and human cells. In C. elegans, sams-1 decrease or loss causes lipid accumulation reminiscent of hepatic steatosis occuring in MAT1A KO mice (Lu et al. PNAS 2001), suggesting models for lipid accumulation in sams-1 animals may be relevant to hepatic steatosis in mammals. Because the 1CC is implicated in multiple fatty liver models and metabolites such as folate or choline are administered as treatments for disease, it is crucial to understand the connections between the 1CC and lipid biosynthesis.

    We are interested in how lipid homeostasis is affected by genetic or dietary changes in 1CC function and how SBP-1/SREBP affects cellular processes such as epigenetic modification by regulating the supply of methyl donors. These projects will include mechanistic studies in mammalian cell culture, in vivo studies in mouse liver as well as genetics screens for discovery in C. elegans. In our studies of SREBP regulation by SIRT1 (Walker, et al. 2010, Genes and Development) and of SREBP regulation of the 1CC (Walker, A., Jacobs, R. et al., Cell, 2011), this combination of models has allowed us to rapidly establish functional biological relationships between pathways in C. elegans, then determine relevance to mammalian physiology and precise molecular mechanisms in mouse knockout or human cell culture models. These types of experiments are important for determining mechanistic relationships between metabolic pathways and cellular function, and furthermore, will aid in our understanding about how these pathways contribute to human disorders such as metabolic syndrome.

    Amy walker  - worms

    Figure. In C. elegans, SBP-1-Dependent Lipogenesis and Gene Expression Are Increased after sams-1(RNAi)

    (A) RNAi knockdown of sams-1 revealed large refractile droplets in the intestine and body cavity by Nomarski optics.

    Amy Walker - Lipid

    Collapse Rotation Projects

    Determine links between SREBPs, SAMe levels and epigenetic regulation

    Methylation of histones or DNA affects gene expression at local as well as global levels. The major cellular methyl donor, s-adenosylmethionine (SAMe) is produced by the folate or 1-carbon (1C) cycle. 1CC function may be affected by dietary levels of folate, methionine, choline or betaine, genetic polymorphisms, or alcohol intake, linking potential for epigenetic modification in cancer progression to food intake and metabolism. Physiological limitation of 1CC function has multiple deleterious physiological effects from birth defects to the development of hepatosteatosis and has also been linked to hepatic and colon cancer. While many studies have shown that the availability of methyl donors may dramatically affect human disease, the mechanisms governing SAMe production and epigenetic modification are much less clear. We hypothesize that modulation of SBP-1 function affecting sams-1 expression will also alter methyl group levels and subsequently, histone modification, leading to changes in gene expression relevant to overall nutritional homeostasis. We will determine if modulation of SAMe levels through SBP-1 effects histone methylation at nutritionally important promoters and examine how diet quality and dietary supplementation affect SBP-1 activity by evaluating histone methylation, in addition to employing biological assays for epigenetic changes in gene expression. We will also use unbiased assays such as ChIP-Seq to identify genes whose expression levels are linked to epigenetic changes after sbp-1 RNAi, selecting those with roles in metabolism for further study. These studies will provide a basis for understanding how lipid homeostasis and other dietary influences affect SAMe production and how those are linked to increased lipid accumulation in C. elegans. Future studies will extend these models to mammalian systems to investigate how these changes predispose hepatosteatosis, a component of metabolic syndrome in humans. Figure 2

    Determine mechanisms for differential regulation of SREBP-1 and SREBP-2 by PC-based feedback

    In recent studies, we have found that inactive precursors for SREBP-1 are cleaved, accumulate in the nucleus and activate lipogenic transcription programs when membrane changes linked to low PC levels alter localization of SREBP-activating proteases (see Research Interests). We also found that SREBP-2 was resistant to this regulation (Figure 1), and note that while mouse models of PC depletion are associated with hepatic steatosis, cholesterol levels are not necessarily affected (Jacobs, et al. 2008, JBC). We will determine the mechanisms of this differential regulation which will be important for understanding how lipid or cholesterol synthesis may be inappropriately stimulated in metabolic disease.

    Figure 1 
    Figure 1: Depletion of PC biosynthesis enzymes in HepG2 human hepatoma cells causes nuclear localization of SREBP-1, but not SREBP-2. Yellow line shows cell boundary


    Identify cellular responses to decreased SAMe production

    Our studies in C. elegans showed that SREBP transcriptional activators could control expression 1CC genes. These studies are important because they demonstrate that levels of these critical enzymes mRNAa are not controlled as a “housekeeping function” but are instead are coordinated with other cellular processes. We have developed two models for 1CC dysfunction in C. elegans, a genetic model based on loss of function (lof) of sams-1, a SBP-1/SREBP responsive gene encoding the enzyme for producing the methyl donor SAMe and a dietary model in which C. elegans are fed bacteria unable to synthesize folate. In both of these models, transcription of lipogenic genes are highly increased and sams-1(lof) worms accumulate large lipid droplets, mimicking aspects of fatty liver disease in mammals. These models will allow use genetic screens as a tool for identifying 1) other regulatory pathways affecting SAMe production or utilization and 2) cellular responses that limit lipogenesis when methyl donor levels are low.

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Holdorf AD, Higgins DP, Hart AC, Boag PR, Pazour GJ, Walhout AJM, Walker AK. WormCat: An Online Tool for Annotation and Visualization of Caenorhabditis elegans Genome-Scale Data. Genetics. 2019 Dec 06. PMID: 31810987.
      View in: PubMed
    2. Ding W, Higgins DP, Yadav DK, Godbole AA, Pukkila-Worley R, Walker AK. Stress-responsive and metabolic gene regulation are altered in low S-adenosylmethionine. PLoS Genet. 2018 Nov 28; 14(11):e1007812. PMID: 30485261.
      View in: PubMed
    3. Walker AK. 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver. Trends Endocrinol Metab. 2017 Jan; 28(1):63-72. PMID: 27789099.
      View in: PubMed
    4. Walker AK. Germ Cells Need Folate to Proliferate. Dev Cell. 2016 Jul 11; 38(1):8-9. PMID: 27404353.
      View in: PubMed
    5. Smulan LJ, Ding W, Freinkman E, Gujja S, Edwards YJ, Walker AK. Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation. Cell Rep. 2016 Jun 28; 16(1):9-18. PMID: 27320911.
      View in: PubMed
    6. Ding W, Smulan LJ, Hou NS, Taubert S, Watts JL, Walker AK. s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways. Cell Metab. 2015 Oct 06; 22(4):633-45. PMID: 26321661.
      View in: PubMed
    7. Amy K Walker & Anders M Näär. Clinical Lipidology. SREBPs: regulators of cholesterol/lipids as therapeutic targets in metabolic disorders, cancers and viral diseases. 2012; 1(7):27-36.
    8. Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, Shioda T, Hansen M, Yang F, Niebergall LJ, Vance DE, Tzoneva M, Hart AC, Näär AM. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011 Nov 11; 147(4):840-52. PMID: 22035958.
      View in: PubMed
    9. Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi-Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Näär AM. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 2010 Jul 01; 24(13):1403-17. PMID: 20595232.
      View in: PubMed
    10. Blackwell TK, Walker AK. OMA-gosh, where's that TAF? Cell. 2008 Oct 3; 135(1):18-20. PMID: 18854150.
      View in: PubMed
    11. Walker AK, Boag PR, Blackwell TK. Transcription reactivation steps stimulated by oocyte maturation in C. elegans. Dev Biol. 2007 Apr 1; 304(1):382-93. PMID: 17291483.
      View in: PubMed
    12. Blackwell TK, Walker AK. Transcription mechanisms. WormBook. 2006 Sep 05; 1-16. PMID: 18050436.
      View in: PubMed
    13. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006 Aug 10; 442(7103):700-4. PMID: 16799563.
      View in: PubMed
    14. Walker AK, Shi Y, Blackwell TK. An extensive requirement for transcription factor IID-specific TAF-1 in Caenorhabditis elegans embryonic transcription. J Biol Chem. 2004 Apr 9; 279(15):15339-47. PMID: 14726532.
      View in: PubMed
    15. Blackwell TK, Walker AK. Transcription elongation: TLKing to chromatin? Curr Biol. 2003 Dec 2; 13(23):R915-6. PMID: 14654017.
      View in: PubMed
    16. Takagi T, Walker AK, Sawa C, Diehn F, Takase Y, Blackwell TK, Buratowski S. The Caenorhabditis elegans mRNA 5'-capping enzyme. In vitro and in vivo characterization. J Biol Chem. 2003 Apr 18; 278(16):14174-84. PMID: 12576476.
      View in: PubMed
    17. Walker AK, Blackwell TK. A broad but restricted requirement for TAF-5 (human TAFII100) for embryonic transcription in Caenorhabditis elegans. J Biol Chem. 2003 Feb 21; 278(8):6181-6. PMID: 12458202.
      View in: PubMed
    18. Shim EY, Walker AK, Shi Y, Blackwell TK. CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002 Aug 15; 16(16):2135-46. PMID: 12183367.
      View in: PubMed
    19. Shim EY, Walker AK, Blackwell TK. Broad requirement for the mediator subunit RGR-1 for transcription in the Caenorhabditis elegans embryo. J Biol Chem. 2002 Aug 23; 277(34):30413-6. PMID: 12089139.
      View in: PubMed
    20. Blackwell TK, Walker AK. Getting the right dose of repression. Genes Dev. 2002 Apr 1; 16(7):769-72. PMID: 11937484.
      View in: PubMed
    For assistance with using Profiles, please refer to the online tutorials or contact UMMS Help Desk or call 508-856-8643.
    Walker's Networks
    Click the "See All" links for more information and interactive visualizations!
    Concepts Expand Description
    Co-Authors Expand Description
    Similar People Expand Description
    Same Department Expand Description
    Physical Neighbors Expand Description