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    Last Name

    Peter Lawrence Jones PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCell and Developmental Biology
    AddressWellstone Program
    55 Lake Avenue North
    Worcester MA 01655
      Other Positions
      InstitutionUMMS - School of Medicine

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology


        Department of Cell and Developmental Biology  / Jones Lab Website


        Academic Background  

        Associate Professor - University of Massachusetts Medical School
        Research: Epigenetics; Muscle development and disease, FSHD; Rett Syndrome

        Affiliate Investigator - Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center for FSHD

        Principal Scientist - Boston Biomedical Research Institute

        Assistant Professor - Department of Cell and Developmental Biology - University of Illinois at Urbana-Champaign

        Postdoctoral fellow - Laboratory of Molecular Embryology, NICHD, NIH, Bethesda, MD.  Mentors: Alan P. Wolffe and Yun-bo Shi
        Research: Epigenetics, chromatin, biochemistry

        Emory University, Atlanta, GA - Program in Genetics and Molecular Biology
        Degree: PhD in Eukaryotic gene regulation

        Miami University, Oxford, OH
        Degree: B.A. in Microbiology

        Epigenetic Gene and Genome Regulation

        Facioscapulohumeral muscular dystrophy (FSHD) is a model epigenetic disease

        All forms of FSHD are linked by epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite array. Two true epigenetic regulatory and memory mechanisms, DNA methylation and Polycomb/Trithorax Group regulation, are the primary mediators of maintaining the repressive chromatin state of the FSHD locus in healthy individuals.  These mechanisms are disrupted in FSHD-affected subjects resulting in the region being more epigenetically relaxed and amenable to local gene expression. Additional regulatory mechanisms functioning in the region include histone post-translational modifications, chromatin remodeling, lncRNAs, repeat-induced gene silencing, RNA-directed DNA methylation, nuclear organization, telomere position effect, and trans chromosomal interactions. Interestingly, the epigenetic status and stability of this region is variable between individuals with FSHD due to genetic changes in genes encoding epigenetic regulatory proteins (modifiers of FSHD severity) and/or differences in the efficiency of establishing the epigenetic stateof the region during development.   However, seemingly small differences in one’s epigenetic status of a pathogenic 4q35 D4Z4 array can have a profound impact on clinical outcome and correlates with overall FSHD disease severity.  Thus, clinical FSHD is essentially an epigenetic disease and provides an excellent opportunity to investigate many broadly applicable epigenetic mechanisms of gene and genome regulation.

        Molecular mechanisms of FSHD pathology

        FSHD is the most prevalent myopathy afflicting women, men, children and adults of all ages.  FSHD is an autosomal dominant disease marked by slow but progressive atrophy in specific muscle groups in the face, upper arms, abdomen, hip girdle, and legs with individuals often showing bilateral asymmetry in muscle weakness.  There is a wide range in both the age of disease onset and clinical severity, from the extremely severe infantile form (IFSHD), to the more common young adult onset FSHD manifesting in the second or third decade, to the individuals who show symptoms only much later in life, if ever.  Initial symptoms often causing one to seek clinical help are difficulty raising ones arms above shoulder level, facial weakness and foot drop.  Additional non-muscular symptoms that appear later in the disease progression include high-frequency hearing loss in more than half of all diagnosed cases, and vision problems in ~1% of patients.  With ~20% of FSHD patients becoming wheelchair-bound as young adults, the personal, social, and economic costs of this disease are enormous, and no effective therapies exist.

        FSHD is a genetic disease linked to chromosome 4q35 with a strong epigenetic component (Figure 1). FSHD research has now entered an important new stage as the DUX4 gene has emerged from studies in multiple laboratories, including our own, as the near consensus FSHD candidate gene whose misexpression is necessary for developing pathology. The DUX4gene is present in numerous copies in the genome as each 3.3kb repeat unit of a D4Z4 repeat array contains a DUX4 gene and large D4Z4 macrosatellite arrays are found in several places in the genome. However, only the DUX4 gene in the distal D4Z4 repeat of a permissive 4q35 subtelomeric array can stably express pathogenic transcripts.  The current evidence supports a model in which aberrant stable expression of the DUX4 mRNA splicing variant, termed DUX4-fl (fl = full-length), in skeletal muscle is required for FSHD pathology. This pathogenic mRNA encodes a transcription factor, DUX4-FL, whose expression leads to additional aberrant expression of downstream genes in FSHD muscle.  Expression of DUX4-fl per se is not necessarily causal for FSHD as healthy unaffected individuals occasionally express DUX4-fl mRNA and protein in muscle, albeit at much lower levels than seen in FSHD muscle.  This suggests a quantitative model for DUX4-fl expression leading to FSHD pathology whereby low expression levels are tolerated by certain individuals and higher levels beyond a threshold result in FSHD pathology.
        The primary driver of FSHD pathology is the epigenetic status of a permissive (A type subtelomere) 4q35 D4Z4 macrosatellite array.  Pathogenic changes in the epigenetic status of the 4q35 D4Z4 array occur through several mechanisms including large deletions within the repeats (FSHD1), mutations in genes affecting DNA methylation and heterochromatin structure (FSHD2), or a combination of both.  Regardless of the mechanism for dysregulation, these epigenetic changes result in the increased aberrant expression of DUX4-fl. 
        Interestingly, a number of seemingly healthy individuals have been found to possess the FSHD1 genetic lesion combined with a permissive 4q subtelomere yet show no clinical manifestation of the disease.  Myogenic cells from these individuals show a wide range of DUX4-fl expression from very low, similar to healthy individuals, to levels equivalent to those found in clinically affected FSHD individuals.  In addition, we have found that the epigenetic relaxation of the D4Z4 array is highly variable among genetically FSHD1 individuals, including those clinically affected as well as disease non-manifesting subjects. This indicates the existence of multiple modifier genes functioning at two levels; upstream, regulating the level of DUX4-fl expression (epigenetic modifiers) and downstream, regulating the function of DUX4-fl.  Thus, in addition to DUX4-fl itself, there are a number of additional potential targets for therapeutic development.

        Generation of FSHD-like model organisms

        A major gap in the FSHD field is the lack of phenotypic FSHD-like model organisms based on DUX4-fl expression.  This is in large part due to two large hurdles: 1) DUX4-D4Z4 is not conserved outside of old world primates, and 2) exogenous expression of DUX4-fl, even at extremely low levels, is highly cytotoxic to somatic cells of all vertebrates tested including human, mouse, Xenopus and zebrafish.  However, since many of the DUX4-fl gene targets and adverse effects of expression are conserved, we believe a model organism approach can be successful and valuable. We have successfully generated DUX4-fl expressing Drosophila to use for investigating DUX4-dependent pathways.  In addition, we are generating conditional lines of DUX4-fl expressing mice for developmental studies, investigating pathogenic mechanisms and for preclinical testing of potential FSHD therapeutics.

        The Lab

        Drs. Peter and Takako Jones are a husband-wife team and function effectively as Co-PIs in the lab.  We have a small but highly efficient group and have a number of productive external collaborations.  Our lab has several FSHD research projects: 1) investigating the epigenetic and genetic regulation of DUX4 gene expression and alternative mRNA splicing, 2) investigating additional FSHD candidate genes and transcripts that may be involved in pathology either in concert with or independent of DUX4-fl, 3) generating animal and cell culture models of FSHD using mice, Drosophila, C. elegans and human myogenic cultures, and 4) developing therapeutic strategies to target DUX4-fl mRNA and protein expression and function.
        We wish to thank the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the FSH Society, the Chris Carrino Foundation for FSHD, the Association Francaise contra les Myopathies, the Muscular Dystrophy Association and the Thoracic Foundation (Boston, MA) for their support of our research program.

        Figure 1: FSHD1 and FSHD2 are linked to the epigenetic relaxation of the chromatin at a permissive chromosome 4q35 D4Z4 macrosatellite repeat array.

        Each D4Z4 repeat unit encodes exons 1 and 2 of the DUX4 gene. At least one D4Z4 repeat combined with a permissive “A” type subtelomere is required to develop FSHD.  The permissive “A” type subtelomere encodes a third exon containing a polyadenylation signal that is spliced onto the DUX4 mRNA, thus stabilizing only the DUX4 message transcribed from the terminal D4Z4 repeat.
        *DUX4-fl mRNA and protein have been detected in a small number of healthy control biopsies and myogenic cell cultures; however, the level is significantly lower than what is found in FSHD-affected samples.
        Of note, a number of individuals (estimated up to 1-3%) in the general population have FSHD1-sized deletions and do not exhibit clinical symptoms of FSHD and are referred to as non-manifesting. Their expression levels of DUX4-fl in muscle range from undetectable to levels found in FSHD-affected muscle.  Interestingly, the epigenetic status of these subjects resembles that of healthy subjects as opposed to FSHD-affected.  Therefore, the epigenetic status, and not the genetic status, of the FSHD-associated D4Z4 array closely correlates with disease presentation.

        Department of Cell and Developmental Biology

        Rotation Projects

        We are unable to accept rotation students at this time

        selected publications
        List All   |   Timeline
        1. Jones TI, Parilla M, Jones PL. Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD). PLoS One. 2016; 11(3):e0150938.
          View in: PubMed
        2. Himeda CL, Jones TI, Jones PL. Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies. Trends Pharmacol Sci. 2016 Apr; 37(4):249-51.
          View in: PubMed
        3. Himeda CL, Jones TI, Jones PL. CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy. Mol Ther. 2016 Mar; 24(3):527-35.
          View in: PubMed
        4. Jones TI, King OD, Himeda CL, Homma S, Chen JC, Beermann ML, Yan C, Emerson CP, Miller JB, Wagner KR, Jones PL. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics. 2015; 7:37.
          View in: PubMed
        5. Lek A, Rahimov F, Jones PL, Kunkel LM. Emerging preclinical animal models for FSHD. Trends Mol Med. 2015 May; 21(5):295-306.
          View in: PubMed
        6. Himeda CL, Jones TI, Jones PL. Facioscapulohumeral muscular dystrophy as a model for epigenetic regulation and disease. Antioxid Redox Signal. 2015 Jun 1; 22(16):1463-82.
          View in: PubMed
        7. Jones TI, Yan C, Sapp PC, McKenna-Yasek D, Kang PB, Quinn C, Salameh JS, King OD, Jones PL. Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing. Clin Epigenetics. 2014; 6(1):23.
          View in: PubMed
        8. Himeda CL, Debarnot C, Homma S, Beermann ML, Miller JB, Jones PL, Jones TI. Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy-associated DUX4 gene. Mol Cell Biol. 2014 Jun; 34(11):1942-55.
          View in: PubMed
        9. Mitsuhashi S, E Boyden SE, Estrella EA, Jones TI, Rahimov F, Yu TW, Darras BT, Amato AA, Folkerth RD, Jones PL, Kunkel LM and Kang PB. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy. Neuromuscular Disorders. 2013; 23(12):975-980.
        10. Morgan GT, Jones P, Bellini M. Association of modified cytosines and the methylated DNA-binding protein MeCP2 with distinctive structural domains of lampbrush chromatin. Chromosome Res. 2012 Dec; 20(8):925-42.
          View in: PubMed
        11. Jones TI, Chen JC, Rahimov F, Homma S, Arashiro P, Beermann ML, King OD, Miller JB, Kunkel LM, Emerson CP, Wagner KR, Jones PL. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet. 2012 Oct 15; 21(20):4419-30.
          View in: PubMed
        12. Liu Q, Jones TI, Bachmann RA, Meghpara M, Rogowski L, Williams BD, Jones PL. C. elegans PAT-9 is a nuclear zinc finger protein critical for the assembly of muscle attachments. Cell Biosci. 2012; 2(1):18.
          View in: PubMed
        13. Long SW, Ooi JY, Yau PM, Jones PL. A brain-derived MeCP2 complex supports a role for MeCP2 in RNA processing. Biosci Rep. 2011 Oct; 31(5):333-43.
          View in: PubMed
        14. Sun CY, van Koningsbruggen S, Long SW, Straasheijm K, Klooster R, Jones TI, Bellini M, Levesque L, Brieher WM, van der Maarel SM, Jones PL. Facioscapulohumeral muscular dystrophy region gene 1 is a dynamic RNA-associated and actin-bundling protein. J Mol Biol. 2011 Aug 12; 411(2):397-416.
          View in: PubMed
        15. Bogdanovic O, Long SW, van Heeringen SJ, Brinkman AB, Gómez-Skarmeta JL, Stunnenberg HG, Jones PL, Veenstra GJ. Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis. Genome Res. 2011 Aug; 21(8):1313-27.
          View in: PubMed
        16. Hanel ML, Sun CY, Jones TI, Long SW, Zanotti S, Milner D, Jones PL. Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a dynamic nuclear and sarcomeric protein. Differentiation. 2011 Feb; 81(2):107-18.
          View in: PubMed
        17. Wuebbles RD, Long SW, Hanel ML, Jones PL. Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol. 2010; 3(4):386-400.
          View in: PubMed
        18. Liu Q, Jones TI, Tang VW, Brieher WM, Jones PL. Facioscapulohumeral muscular dystrophy region gene-1 (FRG-1) is an actin-bundling protein associated with muscle-attachment sites. J Cell Sci. 2010 Apr 1; 123(Pt 7):1116-23.
          View in: PubMed
        19. Hanel ML, Wuebbles RD, Jones PL. Muscular dystrophy candidate gene FRG1 is critical for muscle development. Dev Dyn. 2009 Jun; 238(6):1502-12.
          View in: PubMed
        20. Wuebbles RD, Hanel ML, Jones PL. FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy. Dis Model Mech. 2009 May-Jun; 2(5-6):267-74.
          View in: PubMed
        21. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008 Sep 29; 205(10):2409-17.
          View in: PubMed
        22. Wuebbles R, Jones PL. Engineered telomeres in transgenic Xenopus laevis. Transgenic Res. 2007 Jun; 16(3):377-84.
          View in: PubMed
        23. Beenders B, Jones PL, Bellini M. The tripartite motif of nuclear factor 7 is required for its association with transcriptional units. Mol Cell Biol. 2007 Apr; 27(7):2615-24.
          View in: PubMed
        24. Wang Y, Jorda M, Jones PL, Maleszka R, Ling X, Robertson HM, Mizzen CA, Peinado MA, Robinson GE. Functional CpG methylation system in a social insect. Science. 2006 Oct 27; 314(5799):645-7.
          View in: PubMed
        25. Insights into social insects from the genome of the honeybee Apis mellifera. Nature. 2006 Oct 26; 443(7114):931-49.
          View in: PubMed
        26. Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S, El-Osta A. Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing. Nat Genet. 2005 Mar; 37(3):254-64.
          View in: PubMed
        27. Jones PL, Shi YB. N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear hormone receptors. Curr Top Microbiol Immunol. 2003; 274:237-68.
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        28. Sachs LM, Jones PL, Havis E, Rouse N, Demeneix BA, Shi YB. Nuclear receptor corepressor recruitment by unliganded thyroid hormone receptor in gene repression during Xenopus laevis development. Mol Cell Biol. 2002 Dec; 22(24):8527-38.
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        29. Jones PL, Wade PA, Wolffe AP. Purification of MeCP2-containing deacetylase from Xenopus laevis. Methods Mol Biol. 2002; 200:131-41.
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        30. Stunkel W, Ait-Si-Ali S, Jones PL, Wolffe AP. Programming the transcriptional state of replicating methylated dna. J Biol Chem. 2001 Jun 8; 276(23):20743-9.
          View in: PubMed
        31. Jones PL, Sachs LM, Rouse N, Wade PA, Shi YB. Multiple N-CoR complexes contain distinct histone deacetylases. J Biol Chem. 2001 Mar 23; 276(12):8807-11.
          View in: PubMed
        32. Jones PL, Wade PA, Wolffe AP. Purification of the MeCP2/histone deacetylase complex from Xenopus laevis. Methods Mol Biol. 2001; 181:297-307.
          View in: PubMed
        33. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000 Jul; 25(3):338-42.
          View in: PubMed
        34. Sachs LM, Damjanovski S, Jones PL, Li Q, Amano T, Ueda S, Shi YB, Ishizuya-Oka A. Dual functions of thyroid hormone receptors during Xenopus development. Comp Biochem Physiol B Biochem Mol Biol. 2000 Jun; 126(2):199-211.
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        35. Jones PL, Wolffe AP. Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol. 1999 Oct; 9(5):339-47.
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        36. Vermaak D, Wade PA, Jones PL, Shi YB, Wolffe AP. Functional analysis of the SIN3-histone deacetylase RPD3-RbAp48-histone H4 connection in the Xenopus oocyte. Mol Cell Biol. 1999 Sep; 19(9):5847-60.
          View in: PubMed
        37. Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet. 1999 Sep; 23(1):62-6.
          View in: PubMed
        38. Wolffe AP, Jones PL, Wade PA. DNA demethylation. Proc Natl Acad Sci U S A. 1999 May 25; 96(11):5894-6.
          View in: PubMed
        39. Wade PA, Jones PL, Vermaak D, Wolffe AP. Purification of a histone deacetylase complex from Xenopus laevis: preparation of substrates and assay procedures. Methods Enzymol. 1999; 304:715-25.
          View in: PubMed
        40. Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998 Jul 2; 8(14):843-6.
          View in: PubMed
        41. Shi YB, Sachs LM, Jones P, Li Q, Ishizuya-Oka A. Thyroid hormone regulation of Xenopus laevis metamorphosis: functions of thyroid hormone receptors and roles of extracellular matrix remodeling. Wound Repair Regen. 1998 Jul-Aug; 6(4):314-22.
          View in: PubMed
        42. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998 Jun; 19(2):187-91.
          View in: PubMed
        43. Wade PA, Jones PL, Vermaak D, Veenstra GJ, Imhof A, Sera T, Tse C, Ge H, Shi YB, Hansen JC, Wolffe AP. Histone deacetylase directs the dominant silencing of transcription in chromatin: association with MeCP2 and the Mi-2 chromodomain SWI/SNF ATPase. Cold Spring Harb Symp Quant Biol. 1998; 63:435-45.
          View in: PubMed
        44. Jones PL, Ping D, Boss JM. Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol Cell Biol. 1997 Dec; 17(12):6970-81.
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        45. Smith ER, Jones PL, Boss JM, Merrill AH. Changing J774A.1 cells to new medium perturbs multiple signaling pathways, including the modulation of protein kinase C by endogenous sphingoid bases. J Biol Chem. 1997 Feb 28; 272(9):5640-6.
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        46. Ping D, Jones PL, Boss JM. TNF regulates the in vivo occupancy of both distal and proximal regulatory regions of the MCP-1/JE gene. Immunity. 1996 May; 4(5):455-69.
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        47. Jones PL, Kucera G, Gordon H, Boss JM. Cloning and characterization of the murine manganous superoxide dismutase-encoding gene. Gene. 1995 Feb 14; 153(2):155-61.
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