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Thu 12/5/2019 11:00AM - 12:00PM EOH Journal Club Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis EOH Journal Club Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis Thu 12/5/2019 11:00AM - 12:00PM 4140 Public Health, Young Seminar Room Presenter: Rushikesh Deshpande Paper: Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis Authors: Yandong Lai, Xiuying Li, Tiao Li, Yan Chen, Chen Long, Toru Nyunoya, Kong Chen,Georgios D. Kitsios,Seyed Mehdi Nouraie,Yingze Zhang, Bryan J. McVerry, Janet S. Lee,Rama K. Mallampalli, and Chunbin Zou Abstract: Onehallmark of sepsis is a reduced number of lymphocytes, termed lymphopenia,that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by epigenetically modulating chromatin architecture, however, the role of these enzymes in lymphopenia remains elusive. In this study, we identified that a chromatin modulator Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) that is elevated systemically inseptic patients and experimental sepsis, and is crucialfor inducing T-lymphocyte apoptosis.An E3 ubiquitin ligase SCFFBXO9 docks on PRMT4 via a phosphodegron to ubiquitinate the protein at K228 for ubiquitin proteasomal degradation. High PRMT4 expression resulted from reduced levels of SCFFBXO9 that led to increased lymphocyte cell death after Escherichia coliorlipopolysaccharide(LPS) exposure. Ectopic expression of PRMT4 protein caused substantially mphocytedeathvia caspase 3 mediated cell death signaling, and knockout of PRMT4 abolished LPS mediated lymphocyte cell death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. These findings demonstrate a previously uncharacterized role of a key chromatin modulator in lymphocytesurvival that may shed light on devising unique therapeutic modalities to lessen severity of septic immunosuppression. 4140 Public Health, Young Seminar Room
Fri 12/6/2019 1:00PM - 2:00PM EOH Seminar Series Role of Oxidative DNA damage in telomere maintenance: Implications for Aging and Cancer EOH Seminar Series Role of Oxidative DNA damage in telomere maintenance: Implications for Aging and Cancer Fri 12/6/2019 1:00PM - 2:00PM A719 Public Health A719 Public Health

Event

Thu 12/5/2019 11:00AM - 12:00PM
EOH Journal Club
Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis EOH Journal Club
Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis
Thu 12/5/2019 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Rushikesh Deshpande

Paper: Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis

Authors: Yandong Lai, Xiuying Li, Tiao Li, Yan Chen, Chen Long, Toru Nyunoya, Kong Chen,Georgios D. Kitsios,Seyed Mehdi Nouraie,Yingze Zhang, Bryan J. McVerry, Janet S. Lee,Rama K. Mallampalli, and Chunbin Zou

Abstract:
Onehallmark of sepsis is a reduced number of lymphocytes, termed lymphopenia,that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by epigenetically modulating chromatin architecture, however, the role of these enzymes in lymphopenia remains elusive. In this study, we identified that a chromatin modulator Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) that is elevated systemically inseptic patients and experimental sepsis, and is crucialfor inducing T-lymphocyte apoptosis.An E3 ubiquitin ligase SCFFBXO9 docks on PRMT4 via a phosphodegron to ubiquitinate the protein at K228 for ubiquitin proteasomal degradation. High PRMT4 expression resulted from reduced levels of SCFFBXO9 that led to increased lymphocyte cell death after Escherichia coliorlipopolysaccharide(LPS) exposure. Ectopic expression of PRMT4 protein caused substantially mphocytedeathvia caspase 3 mediated cell death signaling, and knockout of PRMT4 abolished LPS mediated lymphocyte cell death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. These findings demonstrate a previously uncharacterized role of a key chromatin modulator in lymphocytesurvival that may shed light on devising unique therapeutic modalities to lessen severity of septic immunosuppression.

4140 Public Health, Young Seminar Room

Fri 12/6/2019 1:00PM - 2:00PM
EOH Seminar Series
Role of Oxidative DNA damage in telomere maintenance: Implications for Aging and Cancer EOH Seminar Series
Role of Oxidative DNA damage in telomere maintenance: Implications for Aging and Cancer
Fri 12/6/2019 1:00PM - 2:00PM
A719 Public Health

A719 Public Health

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EOH Journal Club

Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health

Thursday 11/29 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Yi (Emma) Lu

Paper: Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice

Authors: Deirdre K. Tucker, Schantel Hayes Bouknight, Sukhdev S. Brar, Grace E. Kissling, and Suzanne E. Fenton

Abstract:
BACKGROUND:
Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives.

OBJECTIVES:
This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S(BPS), could affect female pubertal mammary gland development and long-term mammary health in mice.

METHODS:
Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, 50 mg = kg), BPAF (0.05, 0.5, 5 mg = kg), or BPS (0.05, 0.5, 5 mg = kg) via oral gavage between gestation days 10–17. Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points.

RESULTS:
In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood. By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prom-inent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas. Effects were especially prominent in the BPAF 5 mg = kg and BPS 0: 5mg = kg groups. Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls.

CONCLUSIONS:
These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than thatobserved in vehicle- and BPA-exposed animals

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Last Updated On Monday, October 22, 2018 by Orbell, Adam W
Created On Monday, October 15, 2018