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Amy K Walker PhD

TitleAssociate Professor
InstitutionUMass Chan Medical School
DepartmentProgram in Molecular Medicine
AddressUMass Chan Medical School
373 Plantation Street Two Biotech Suite 137
Worcester MA 01605
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentProgram in Molecular Medicine

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program

    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 
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    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

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    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.

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    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.
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    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Fanelli MJ, Welsh CM, Lui DS, Smulan LJ, Walker AK. Immunity-linked genes are stimulated by a membrane stress pathway linked to Golgi function and the ARF-1 GTPase. Sci Adv. 2023 12 08; 9(49):eadi5545. PMID: 38055815.
      Citations:    Fields:    Translation:AnimalsCells
    2. Alexander KD, Ramachandran S, Biswas K, Lambert CM, Russell J, Oliver DB, Armstrong W, Rettler M, Liu S, Doitsidou M, B?nard C, Walker AK, Francis MM. The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling. Nat Commun. 2023 11 18; 14(1):7520. PMID: 37980357.
      Citations:    Fields:    Translation:HumansAnimalsCells
    3. Godbole AA, Gopalan S, Nguyen TK, Munden AL, Lui DS, Fanelli MJ, Vo P, Lewis CA, Spinelli JB, Fazzio TG, Walker AK. S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress. Elife. 2023 02 09; 12. PMID: 36756948.
      Citations: 1     Fields:    Translation:Animals
    4. Higgins DP, Weisman CM, Lui DS, D'Agostino FA, Walker AK. Defining characteristics and conservation of poorly annotated genes in Caenorhabditis elegans using WormCat 2.0. Genetics. 2022 07 30; 221(4). PMID: 35587742.
      Citations: 10     Fields:    Translation:HumansAnimals
    5. 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. 2020 02; 214(2):279-294. PMID: 31810987.
      Citations: 59     Fields:    Translation:AnimalsCells
    6. 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 11; 14(11):e1007812. PMID: 30485261.
      Citations: 13     Fields:    Translation:AnimalsCells
    7. Walker AK. 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver. Trends Endocrinol Metab. 2017 01; 28(1):63-72. PMID: 27789099.
      Citations: 15     Fields:    Translation:HumansAnimalsCells
    8. Walker AK. Germ Cells Need Folate to Proliferate. Dev Cell. 2016 07 11; 38(1):8-9. PMID: 27404353.
      Citations:    Fields:    Translation:AnimalsCells
    9. Smulan LJ, Ding W, Freinkman E, Gujja S, Edwards YJK, Walker AK. Cholesterol-Independent SREBP-1 Maturation Is Linked to ARF1 Inactivation. Cell Rep. 2016 06 28; 16(1):9-18. PMID: 27320911.
      Citations: 27     Fields:    Translation:HumansCells
    10. 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.
      Citations: 61     Fields:    Translation:AnimalsCells
    11. 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. View Publication.
    12. 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, N??r AM. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011 Nov 11; 147(4):840-52. PMID: 22035958.
      Citations: 214     Fields:    Translation:HumansAnimalsCells
    13. 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, N??r 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.
      Citations: 189     Fields:    Translation:HumansAnimalsCells
    14. Blackwell TK, Walker AK. OMA-gosh, where's that TAF? Cell. 2008 Oct 03; 135(1):18-20. PMID: 18854150.
      Citations:    Fields:    Translation:AnimalsCells
    15. Walker AK, Boag PR, Blackwell TK. Transcription reactivation steps stimulated by oocyte maturation in C. elegans. Dev Biol. 2007 Apr 01; 304(1):382-93. PMID: 17291483.
      Citations: 26     Fields:    Translation:AnimalsCells
    16. Blackwell TK, Walker AK. Transcription mechanisms. WormBook. 2006 Sep 05; 1-16. PMID: 18050436.
      Citations: 9     Fields:    Translation:AnimalsCells
    17. 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, N??r AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006 Aug 10; 442(7103):700-4. PMID: 16799563.
      Citations: 217     Fields:    Translation:HumansAnimalsCells
    18. Piper BJ, Fraiman JB, Meyer JS. Repeated MDMA ("Ecstasy") exposure in adolescent male rats alters temperature regulation, spontaneous motor activity, attention, and serotonin transporter binding. Dev Psychobiol. 2005 Sep; 47(2):145-57. PMID: 12183367.
      Citations: 91     Fields:    Translation:AnimalsCells
    19. 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 09; 279(15):15339-47. PMID: 14726532.
      Citations: 10     Fields:    Translation:HumansAnimalsCells
    20. Blackwell TK, Walker AK. Transcription elongation: TLKing to chromatin? Curr Biol. 2003 Dec 02; 13(23):R915-6. PMID: 14654017.
      Citations: 3     Fields:    Translation:AnimalsCells
    21. 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.
      Citations: 9     Fields:    Translation:HumansAnimalsCells
    22. 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.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    23. 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.
      Citations: 8     Fields:    Translation:AnimalsCells
    24. Blackwell TK, Walker AK. Getting the right dose of repression. Genes Dev. 2002 Apr 01; 16(7):769-72. PMID: 11937484.
      Citations:    Fields:    Translation:AnimalsCells
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