Sign in to edit your profile (add interests, mentoring, photo, etc.)
    Keywords
    Last Name
    Institution

    Peter Lawrence Jones PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentCell and Developmental Biology
    AddressWellstone Program
    55 Lake Avenue North
    Worcester MA 01655
    Phone774-455-1581
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentNeurology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCell Biology

        Overview 
        Narrative

        Department of Cell and Developmental Biology / Wellstone Program

        Academic Background

        2013-Present
        Associate Professor - University of Massachusetts Medical School
        Research: Epigenetics; Muscle development and disease, FSHD; Rett Syndrome

        2011-Present
        Affiliate Investigator - Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center for FSHD

        2010-2013
        Principal Scientist - Boston Biomedical Research Institute

        2001-2010
        Assistant Professor - Department of Cell and Developmental Biology - University of Illinois at Urbana-Champaign

        1997-2001
        Postdoctoral fellow - Laboratory of Molecular Embryology, NICHD, NIH, Bethesda, MD.  Mentors: Alan P. Wolffe and Yun-bo Shi
        Research: Epigenetics, chromatin, biochemistry

        1991-1997
        Emory University, Atlanta, GA - Program in Genetics and Molecular Biology
        Degree: PhD in Eukaryotic gene regulation

        1987-1991
        Miami University, Oxford, OH
        Degree: B.A. in Microbiology

        Epigenetic gene and genome regulation

        Facioscapulohumeral muscular dystrophy (FSHD) as a model for epigenetic gene and genome regulation

        All forms of FSHD are linked by epigenetic dysregulation of the 4q35 D4Z4 macrosatellite array.  Many epigenetic regulatory and memory mechanisms are known to be involved in FSHD, including DNA methylation, Polycomb Group/Trithorax silencing and activation, histone modifications, chromatin remodeling, lncRNAs, sncRNAs, repeat-induced gene silencing and telomere position effect.  Additional mechanisms are likely to be involved including RNA-directed DNA methylation and gene silencing, nuclear organization, and trans chromosomal interactions.  Healthy individuals have an epigenetically silent chromatin structure at the 4q35 D4Z4 array whereas FSHD affected subjects have a more permissive and euchromatic structure.  Thus, comparing the healthy and FSHD-affected situations provides an excellent model for investigating 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 many 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
        Wellstone Program



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. 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 Mar 17.
          View in: PubMed
        2. 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.
        3. 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
        4. 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
        5. 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
        6. 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 1; 31(5):333-43.
          View in: PubMed
        7. 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
        8. 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
        9. 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
        10. 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
        11. 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
        12. 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
        13. 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
        14. 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
        15. Wuebbles R, Jones PL. Engineered telomeres in transgenic Xenopus laevis. Transgenic Res. 2007 Jun; 16(3):377-84.
          View in: PubMed
        16. 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
        17. 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
        18. Insights into social insects from the genome of the honeybee Apis mellifera. Nature. 2006 Oct 26; 443(7114):931-49.
          View in: PubMed
        19. 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
        20. 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.
          View in: PubMed
        21. 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.
          View in: PubMed
        22. Jones PL, Wade PA, Wolffe AP. Purification of MeCP2-containing deacetylase from Xenopus laevis. Methods Mol Biol. 2002; 200:131-41.
          View in: PubMed
        23. 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
        24. 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
        25. 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
        26. 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
        27. 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.
          View in: PubMed
        28. Jones PL, Wolffe AP. Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol. 1999 Oct; 9(5):339-47.
          View in: PubMed
        29. 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
        30. 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
        31. 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
        32. 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
        33. 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
        34. 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
        35. 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
        36. 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
        37. 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.
          View in: PubMed
        38. 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.
          View in: PubMed
        39. 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.
          View in: PubMed
        40. 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.
          View in: PubMed
        For assistance with using Profiles, please refer to the online tutorials or contact UMMS Help Desk or call 508-856-8643.
        Peter's Networks
        Click the "See All" links for more information and interactive visualizations!
        Concepts
        _
        Co-Authors
        _
        Similar People
        _
        Same Department
        Physical Neighbors
        _

        This is an official Page/Publication of the University of Massachusetts Worcester Campus
        Office of the Vice Provost for Research, 55 Lake Ave North, Worcester, Massachusetts 01655
        Questions or Comments? Email: publicaffairs@umassmed.edu Phone: 508-856-1572