Denise Juhr

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States

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Publications (3)66.04 Total impact

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    ABSTRACT: Transcription factor-based cellular reprogramming has opened the way to converting somatic cells to a pluripotent state, but has faced limitations resulting from the requirement for transcription factors and the relative inefficiency of the process. We show here that expression of the miR302/367 cluster rapidly and efficiently reprograms mouse and human somatic cells to an iPSC state without a requirement for exogenous transcription factors. This miRNA-based reprogramming approach is two orders of magnitude more efficient than standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse and human miR302/367 iPSCs display similar characteristics to Oct4/Sox2/Klf4/Myc-iPSCs, including pluripotency marker expression, teratoma formation, and, for mouse cells, chimera contribution and germline contribution. We found that miR367 expression is required for miR302/367-mediated reprogramming and activates Oct4 gene expression, and that suppression of Hdac2 is also required. Thus, our data show that miRNA and Hdac-mediated pathways can cooperate in a powerful way to reprogram somatic cells to pluripotency.
    Full-text · Article · Apr 2011 · Cell stem cell
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    ABSTRACT: Background and aims: Congenital heart defects (CHDs) represent the most common structural birth defect in humans. While the identification of specific genes in these disorders have contributed to our understanding of cardiac development, they have not provided significant insight into the etiology of common, non-syndromic forms of CHDs. Our goal was to identify the copy number variants (CNVs) associated with CHDs.Methods: We used a systematic approach using high-resolution SNP genotyping arrays to identify CNVs priority ranked based on their potential pathogenicity using a program, Perl Copy Numbers of Potential Interest (PECONPI), developed in our lab. PECONPI identifies disruptions in highly conserved non-coding regions 1 Mb upstream or downstream to known developmental cardiac loci. We screened of 362 probands with CHDs and 3000 controls using PECONPI.Results: We identified over 150 candidate CNVs that meet the criteria: 1) highly or ultra-conservation, 2) within 1 Mb of a candidate locus, and 3) not present in control samples. We identified a cluster of overlapping deletions involving a conserved non-coding element (CNCE) on 2p 13.3 in 7 unrelated probands, 6 with identical 5 Kb deletions and one with a smaller I Kb deletion, not seen in 3000 controls. This included 4 with TGA, 1 with TOF, 1 with a vascular ring, and 1 with unbalanced atrioventricular canal.Conclusions: The presence of TGAs in 4/7 (57%) is discordant from the total population screened in which TGAs were present in 46/362 (13%) of the probands. Thus we have identified a novel CNCE for CHD.
    Preview · Article · Nov 2010 · Pediatric Research
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    ABSTRACT: The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.
    Full-text · Article · Aug 2010 · Nature