Jill Fahrner, MD, PhD

Professional Titles

• Director, Epigenetics and Chromatin Clinic

Primary Academic Title

Associate Professor of Genetic Medicine

Background

Centers and Institutes

McKusick-Nathans Institute of Genetic Medicine

Additional Academic Titles

Associate Professor of Pediatrics

Contact for Research Inquiries

733 North Broadway St
Miller Research Building, Suite 409
Baltimore, MD 21205

Research Summary

Dr. Fahrner’s laboratory research uses novel mammalian cell systems and mouse models to elucidate disease mechanisms responsible for Mendelian disorders of the epigenetic machinery (MDEMs) and to identify therapies to treat these conditions. Specifically, her team focuses on Kabuki syndrome 1 and 2 (KS1 and KS2) and Weaver syndrome (WS). KS1 and KS2 are phenocopies of one another but result from mutations in distinct components of the epigenetic machinery, and disruption of both are expected to tip the balance of chromatin toward a more closed, transcriptionally silenced state at target genes. KS2 and WS are molecularly and phenotypically opposing disorders with the former exhibiting growth retardation and resulting from deficiency of the eraser of the H3K27 methylation (H3K27me) silencing mark, and the latter exhibiting overgrowth and resulting from deficiency of the writer of the same H3K27me mark. The Fahrner lab is using mouse models of these related disorders to elucidate mechanisms of abnormal growth. They recently elucidated a novel mechanism of growth retardation in KS1, which results from haploinsufficiency of KMT2D, encoding a histone methyltransferase writer of H3K4 methylation (H3K4me). The mechanism involves disrupted endochondral ossification and precocious chondrocyte differentiation within KS1 mouse growth plates due to reduced deposition of H3K4me3 at a novel target (Shox2). Elucidation of mechanisms of growth retardation in the phenotypically similar disorder KS2, which results from deficiency of the H3K27me eraser KDM6A, is also ongoing. 

The Fahrner lab is particularly interested in well-established MDEMs that involve overgrowth and intellectual disability, namely WS and Sotos syndrome, as well as in novel disorders that they have elucidated. They have created a novel mouse model of WS, characterized the overgrowth phenotype, and are currently elucidating molecular mechanisms of overgrowth. In collaboration with the Baylor-Hopkins Center for Mendelian Genomics, the Fahrner lab elucidated a new disorder, Beck-Fahrner syndrome (BEFAHRS), due to deficiency of TET3. BEFAHRS is a novel category of MDEM because it is the first neurodevelopmental disorder of the DNA demethylation eraser system, and Dr. Fahrner and her team have identified an associated genome-wide DNA methylation profile in blood of affected individuals. The TET3-deficient episignature exhibits DNA hypermethylation and can distinguish affected individuals from controls and from individuals with 46 other disorders. Further characterization of this new disorder and analysis of additional potential novel variants and candidate genes is ongoing and should fuel and expand future research in the Fahrner lab.

Google Scholar

https://scholar.google.com/scholar?start=20&q=Jill+A+Fahrner&hl=en&as_sdt=0,21

PubMed

https://pubmed.ncbi.nlm.nih.gov/?term=FAhrner+JA+%5BAuthor%5D&sort=date

Selected Publications

• Fahrner JA and Bjornsson HT. Mendelian Disorders of the Epigenetic Machinery: Postnatal Malleability and Therapeutic Prospects. Hum Mol Genet 2019 Nov 21;28(R2):R254-R264. PMID: 31595951

• Fahrner JA and Bjornsson HT. Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states. Annual Rev Genomics Hum Genet 2014;15:269-93. PMID: 25184531

• Fahrner JA*, Lin WY, Riddle RC, Boukas L, DeLeon VB, Chopra S, Lad SE, Luperchio TR, Hansen KD, Bjornsson HT*. Precocious Chondrocyte Differentiation Disrupts Skeletal Growth in Kabuki Syndrome Mice. JCI Insight 2019 Oct 17;4(20) e129380. PMID:31557133

• Beck DB, Petracovici A, He C, Moore HW, Louie RJ, Ansar M, Douzgou S, Sithambaram S, Cottrell T, Santos-Cortez RLP, Prijoles EJ, Bend R, Keren B, Mignot C, Nougues MC, Õunap K, Reimand T, Pajusalu S, Zahid M, Saqib MAN, Buratti J, Seaby EG, McWalter K, Telegrafi A, Baldridge D, Shinawi M, Leal SM, Schaefer GB, Stevenson RE,  Banka S, Bonasio R, and Fahrner JA. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. Am J Hum Genet. 2020 Feb 6;106(2):234-245. PMID:31928709

• Harris JR, Fahrner JA. Disrupted epigenetics in the Sotos syndrome neurobehavioral phenotype. Curr Opin Psychiatry. 2019 March; 32(2):55-59. PMID: 30601169

Honors

• Margaret Ellen Nielsen Fellowship Award, Johns Hopkins
• Alice and YT Chen Travel Award, Johns Hopkins
• Musculoskeletal Pilot and Feasibility Award, Baltimore Center for Musculoskeletal Sciences/Johns Hopkins School of Medicine
• William and Ella Owens Medical Research Foundation Award
• ASHG Reviewer's Choice Abstract Award, American Society of Human Genetics
• Johns Hopkins School of Medicine Clinician Scientist Award
• Hartwell Foundation Individual Biomedical Research Award

Graduate Program Affiliations

• Human Genetics Graduate Training Program

Memberships

• American Society of Human Genetics