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OP-1250 Is a Complete Estrogen Receptor

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Cell Division (GO.0051301) Cell Division (GO.0051301) OP-1250 is a Complete Estrogen Receptor Antagonist (CERAN) that Lacks Agonist E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 SRN.927 Fulv E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 SRN.927 Fulv CDC6 CDC6 ERCC6L ERCC6L SPC25 SPC25 NDC80 NDC80 SKA1 SKA1 NCAPG NCAPG KIFC1 KIFC1 Activity on Cell Signaling and Proliferation in Breast Cancer KIF18BCells KIF18B Apoptosis (GO.0006915) CDCA5 CDCA5 SPC24 SPC24 Apoptosis (GO.0006915) KIF2C KIF2C CDK1 CDK1 TACC3 TACC3 SKA3 SKA3 Leslie Hodges-Gallagher, Richard Sun, David C. Myles, Cyrus L. Harmon, Peter J. Kushner BUB1B BUB1B CCNA2 CCNA2 CDCA8 CDCA8 UBE2C UBE2C NUF2 NUF2 CDC20 CDC20 Olema Oncology, San Francisco, CA KIF20A KIF20A NCAPH NCAPH CDC25C CDC25C SPAG5 SPAG5 E2 Lasofox OH.Tam Bazedox ARN.810 RAD1901 AZD.9496 SRN.927 OP.1250 Fulv BIRC5 BIRC5 CDCA7 BUB1 BUB1 E2 Lasofox OH.Tam Bazedox ARN.810 RAD1901 AZD.9496 SRN.927 OP.1250 Fulv The Estrogen Receptor (ER) is a tripartite protein with two Partial antagonists (such as tamoxifen) have a short PIM1 SGO1 SGO1 CDCA7 CERANs shut down both activation MCM2 CCNE2 CCNE2 PIM1 CDC25A BRCA1 CDC25A MCM2 OP-1250 lacks agonist activity on estrogen-HELLSregulated pro-proliferative, anti-apoptotic genes ESPL1 HELLS BRCA1 CENPE CENPE distinct transcriptional activation functions (AF1 and AF2) duration of response for treatment of breast cancer functions (AF1 and AF2) of the ER CDK1 KIF14 ESPL1 KIF14 CDK1 BUB1B OIP5 OIP5 DDIAS ZWINT ZWINT BUB1B TRAIP FBXO5 FBXO5 DDIAS in breast cancer cellsMELK CDC7 CDC7 TRAIP BUB1 KIF11 KIF11 MELK and recruit N-CoR to inactivate AF1 NCAPG2 NCAPG2 BUB1 BIRC5 CCNB2 Tamoxifen DPF1 CCNB2 BIRC5 CENPF CENPF TPX2 DPF1 MAD2L1 MAD2L1 Signaling Estrogen (E2) (partial antagonist, mTOR TPX2 mTOR mTOR A PLSCR1 B G1/S transition (GO.0000082)TPX2 TPX2 Cell Proliferation (GO.0008283) PLSCR1 MTFP1 KNTC1 D Cell Division (GO.0051301)KNTC1 E Apoptosis (GO.0006915) pathways turns on AF2 N-CoR CENPW MTFP1 PIDD1 6 6 CENPW SGSM1 LIG1 LIG1 6 PIDD1 CDCA3 6 PI3K turn on AF1 PI3K PI3K CERAN RPS6KA3 CDCA3 SGSM1 4 FAM83D 4 4 PHLDA2 FAM83D RPS6KA3 4 CERAN PTTG1 PTTG1 Both AF1 and AF2 can TAM (a complete HIP1 2 NEK2 2 2 PHLDA2 NEK2 HIP1 2 MAPK TNFAIP8 CDCA2 CDCA2 MAPK MAPK antagonist) 0 0 TNFAIP8 drive transcription BCL2L12 SMC4 SMC4 0 0 AF1 AF2 G2E3 −2 SGO2 SGO2 BCL2L12 AF1 AF2 AF1 AF2 CSE1L CCNB1 −2 CCNB1 −2 G2E3 AURKA −2 c-SRC KANK2 −4 AURKA CSE1L c-SRC c-SRC SEPTIN3 SEPTIN3 KANK2 −4 on on on CASP2 TUBA1B KLF11 TUBA1B CASP2 CENPJ CENPJ TIAM1 CellE2 DivisionLasofox OH.Tam (GO.0051301)Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 Fulv KLF11 CHEK2 E2 Lasofox OH.Tam Bazedox ARN.810 RAD1901 AZD.9496 OP.1250 Fulv E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 Fulv EGFR E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 CHEK2 Fulv TIAM1 EGFR EGFR DNA PEG3 CCNE1 RRM2 CCNE1 BRCA1 DNA DNA No Cancer Cell RAD21TCF19 TIMELESSORC1 CDC6 PEG3 Proliferation during Proliferation during UHRF1 TIMELESS ERCC6L CDCA7 CKAP2 VRK1 CDC6 VRK1 RAD21 binding TYMS CDT1 SPC25 ESPL1 NCAPD3 NCAPD3 CKAP2 binding binding FGFR Proliferation STK17BMCM10 MCM10 KIF18B CDK1 FGFR Cancer Progression FGFR Cancer Progression ZWILCH ZWILCH STK17B THOC6PIM1 MASTL TYMS SKA1 PIM1 CTSC KIF15 CDC45 MASTL NCAPG THOC6 TIPIN ORC6 TIPIN MCM2 GRAMD4CDK1 MIS18A KIFC1 CTSC IGFR TACC3 CDCA5 MIS18A NDC80 BUB1B MAGI3 CDK2 GRAMD4 IGFR IGFR MKI67 CDK1 CDK2 SPC24 DDIAS Myc, cyclinD1, BCL2, ... FOXO1 HAUS5 MAGI3 KIF2C IQGAP3 6 HAUS5 CDCA5 TRAIP Myc, cyclinD1, BCL2, ... Myc, cyclinD1, BCL2, ... In breast cancer and uterine cells AF1 is UBE2S CDKN3 FOXO1 TGFBR2BUB1B UBE2S CDK1 MELK SHB SPDL1 CDC25A 4 SPDL1 TACC3 TGFBR2 E2F8 PSRC1 MCM2 BIRC5 During cancer progression, activated through signaling pathways MEF2D PSRC1 KIF2C SHB AURKB LRRCC1 CCNE2 BUB1 CASP9DLGAP5 PKMYT1 2 LRRCC1 BUB1B MEF2D BORA CCNA2 TPX2 kinase signaling turns on AF1 CDC25A E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 SRN.927 Fulv CDC7 BORA CARD14 6 RBBP8 CASP9 DPF1 CDC25C FBXO5 RBBP8 CDCA8 CYFIP2 HAUS1CDC6 0 CARD14 TRAIP MCM5 HAUS1 SKA3 PLSCR1 ING4 4 MIS18BP1ERCC6L UBE2C CYFIP2 CERANs block AF1 activity, even in the presence of signaling, preventing cell proliferation STIL SPC25 PCNA −2 MIS18BP1 MTFP1 BNIPL MELK KNSTRN MCM7 KNSTRN NUF2 ING4 PIDD1 2 NCAPD2NDC80 CDC20 6 BIK BUB1 POLA2 NCAPD2 BNIPL SGSM1 CKS2SKA1 POLE2 KIF20A TRAF1CENPF 0 NCAPG CKS2 BIK PHLDA2 SMC2 MCM8 SMC2 NCAPH 4 GADD45GTPX2 KIFC1 MCM6 TRAF1 HIP1 PLK1 SAC3D1 SAC3D1 CDC25C References: 1) Shang and Brown, Science, 29 Mar 2002: Vol. 295, Issue 5564, pp. 2465-2468. 2) Webb, Nguyen, and Kushner, JBC, Vol. 278, 28 Feb 2003, pp. CASP14 −2 KIF18B MCM3 GADD45G TNFAIP8 2 FAM83D TUBB TUBB SPAG5 RASSF6 CDCA5 CCNE1 BIRC5 CASP14 PCNA CKS1B CKS1B BCL2L12 −4 SPC24 DHFR BUB1 RASSF6 0 BBC3 CCNF CCNF RPS6KA3 6912–6920. 3) Fanning, et al., Nature Comm., Jun 2018, Vol. 9:2268. 4) Hodges-Gallagher, SABCS 2019 (poster). MCM7 KIF2C CDK2 SGO1 INPP5D HAUS8 BBC3 G2E3 CKLF CDK1 PRIM1 HAUS8 CDC25A −2 ITGB2 IGFBP4 STOX1 PRIM2 STOX1 INPP5D CSE1L PARD6BTACC3 HELLS FBXO10CKS2 DBF4 PARD6B ITGB2 KANK2 −4 CCND1SKA3 POLE CCNE2 EPHA7POLR3G BUB1B CCND1 CENPE FBXO10 CASP2 SIX2 HAUS3 POLA1 HAUS3 TP53INP1 USP37CCNA2 MCM4 KIF14 EPHA7 KLF11 POLA1 CDCA8 USP37 OIP5 TP53INP1 CKS1B CCSAP RPA2 TIAM1 UBE2C RBBP8 CCSAP ZWINT DTYMK DSN1 PEG3 NUF2 RPA3 DSN1 FBXO5 CDK5R1 HAUS6 RAD21 CDC20 SKP2 HAUS6 CDC7 NASP HAUS2 KIF20A RANBP1 HAUS2 KIF11 CKAP2 SKP2 SMC3 CCND1 SMC3 NCAPG2 STK17B SMC1ANCAPH OP-1250 is a complete antagonist that turns off both AF1 and CSE1L USP37 SMC1A CCNB2 THOC6 Partial agonists increase, or incompletely HAUS4CDC25C IRS2 CDKN2D SPAG5 HAUS4 CENPF CTSC PRKDC MCMBP RPA1 MAD2L1 BIRC5 MCMBP GRAMD4 TFDP1 HAUS7 EIF4EBP1 TPX2 BUB1 HAUS7 SRRT MAD2L2 RCC1 MAD2L2 KNTC1 MAGI3 SGO1 PPAT PA2G4 TUBA1C TUBA1C CENPW FOXO1 CDC14A CDC25BCCNE2 CDKN1C LIG1 6 Apoptosis (GO.0006915) TGFBR2 AF2 of the wild type and mutant ER CDC25ACDKN1A CDC25B block, breast cancer cell proliferation AR REEP4 FAM83D SHB HELLS REEP4 4 CITED2 KMT5A KMT5A CDCA3 MEF2D NEDD1CENPE CDCA2 ERBB4 NEDD1 CARD14 COL4A3BP SMC5KIF14 PTTG1 2 OIP5 SMC5 CYFIP2 DACH1 RCC1 RCC1 NEK2 APC2 RAD21ZWINT SMC4 0 CASP9 FBXO5 RAD21 A ZFP36L2 SEH1L SEH1L SGO2 ING4 120 B CDC7 CCNB1 CAMA-1 A TSPAN1 CKAP5 CKAP5 −2 BNIPL CHRM1 BUB3KIF11 AURKA BIK Partial agonists, but not CERANs, activate AF1 NCAPG2 BUB3 SEPTIN3 Alkaline phosphatase activity is EMP1 CNTRL CNTRL TRAF1 ERBB2 CDC14ACCNB2 TUBA1B CENPF CDC14A CENPJ GADD45G SIPA1 C CCNG2 CCNG2 DDIT4 G2/M transition (GO.0000086)MAD2L1 CHEK2 ITGB2 dependent on AF1 TPX2 CCNE1 RASSF6 % Wild type receptor TIMELESS KNTC1 E2 Lasofox OH.Tam Bazedox ARN.810 RAD1901 AZD.9496 SRN.927 OP.1250 Fulv BBC3 VRK1 100 CENPW CDCA7 INPP5D 125 Figs. 3A-F. Gene expression heatmaps selected for LIG1 6 NCAPD3 ZWILCH PIM1 CASP14 CDCA3 FBXO10 0 50 100 150 200 250 300 FAM83D 4 MASTL MCM2 specific gene ontology terms for genes significantly PTTG1 TIPIN BRCA1 EPHA7 NEK2 2 MIS18A ESPL1 TP53INP1 CDK2 CDCA2 CDK1 regulated by E2 (log2 fold-change over vehicle ≥ 1, adJ. SMC4 0 HAUS5 UBE2S BUB1B SGO2 SPDL1 DDIAS 80 empty vector 100 CCNB1 p ≤ 0.05). Expression was determined by RNA-seQ −2 PSRC1 TRAIP AURKA STOX1 MELK SEPTIN3 PARD6B analysis on CAMA-1 cells treated with 100 pM E2 or 316 TUBA1B BUB1 E2 Lasofox OH.Tam Bazedox RAD1901 ARN.810 AZD.9496 OP.1250 Fulv CCND1 1 185 251 595 CENPJ BIRC5 CDK1 LRRCC1 nM antiestrogen for 24 hours in E2-depleted media. CHEK2 CCNA2 BORA DPF1 CCNE1 CDC25A RBBP8 TPX2 AF1 DBD LBD/AF2 75 TIMELESSCDC25C USP37 PLSCR1 60 VRK1 CIT DSN1 F Cell Cycle Arrest (GO.0007050)MTFP1 NCAPD3 PLK4 CCSAP PIDD1 ZWILCH MELK HAUS3 6 1 Y537S 595 MASTL PKMYT1 HAUS6 SGSM1 FOXM1 RPS6KA3 TIPIN HAUS2 4 Differential gene expression in CAMA-1 cells MIS18A CCNB2 HAUS1 PHLDA2 AF1 DBD LBD/AF2 CDK2 TPX2 6 MIS18BP1 HIP1 2 HMMR 50 HAUS5 KNSTRN TNFAIP8 UBE2S PLK1 4 NCAPD2 0 Proliferation (%E2) upregulated* downregulated* CEP152 BCL2L12 SPDL1 CKS2 40 NEK2 G2E3 1 595 PSRC1 2 SMC2 −2 D538G CCNB1 SAC3D1 CSE1L E2 1286 905 LRRCC1 AURKA AF-1 activity (% E2) 0 TUBB KANK2 −4 BORA CENPJ AF1 DBD LBD/AF2 RBBP8 CHEK2 HAUS8 CASP2 OH-Tamoxifen 372 24 HAUS1 CDK2 −2 CKS1B KLF11 6 25 CCNF MIS18BP1 MASTL E2 Lasofox OH.Tam Bazedox ARN.810 AZD.9496 RAD1901 OP.1250 TIAM1 Fulv KNSTRN HAUS5 HAUS7 4 SMC3 PEG3 CDKN2C 1 282 Lasofoxifene 404 23 NCAPD2 CEP135 SMC1A RAD21 DDIAS 20 CKS2 CEP72 CDKN3 2 HAUS1 HAUS4 CKAP2 Bazedoxifene 250 5 SMC2 MCMBP KIF20A 0 AF1 DBD SAC3D1 BORA STK17B BARD1 CCP110 MAD2L2 TUBB TUBA1C THOC6 TP73 CEP78 MTBP −2 0 AZD9496 143 6 CKS1B CHEK1 CDC25B CTSC CCNF TUBB REEP4 GRAMD4 MYC 179 595 TGFB1 −4 HAUS8 HAUS8 KMT5A MAGI3 RASSF1 RAD1901 160 5 STOX1 HAUS3 NEDD1 FOXO1 PARD6B ALMS1 CDKN2D 0 DBD LBD/AF2 SMC5 TGFBR2 CCND1 FGFR1OP RCC1 MSH2 ARN-810 164 5 HAUS3 CEP76 RAD21 SHB PPP2R3B USP37 ODF2 SEH1L MEF2D PA2G4 CKAP2 CDKN1C Veh 595 CCSAP CKAP5 CASP9 Veh 179 Y537S Fulvestrant 58 11 CNTRL CDKN1A Fulv Fulv DSN1 BUB3 CARD14 IRF6 HAUS6 HAUS6 CNTRL OP-1250 CYFIP2 Endox Endox HAUS2 FOXO4 DBD LBD/AF2 HAUS2 CDC14A ARN-810 OP-1250 13 1 OH-Tam SKP2 ING4 ING4 RAD1901 OH-Tam Lasofox Lasofox Bazedox AZD9496 OP-1250 OP-1250 CCNG2 Endoxifen ARN-810 SMC3 Bazedox AZD9496 ARN-810 AZD9496 RAD1901 TUBG1 HBP1 RAD1901 BNIPL SMC1A HAUS4 INHA Fulvestrant BIK Table 1.
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  • Symplekin and Transforming Acidic Coiled-Coil Containing Protein 3 Support the Cancer Cell Mitotic Spindle

    Symplekin and Transforming Acidic Coiled-Coil Containing Protein 3 Support the Cancer Cell Mitotic Spindle

    SYMPLEKIN AND TRANSFORMING ACIDIC COILED-COIL CONTAINING PROTEIN 3 SUPPORT THE CANCER CELL MITOTIC SPINDLE Kathryn M. Cappell A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctorate of Philosophy in the Department of Pharmacology, School of Medicine. Chapel Hill 2011 Approved by: Advisor: Dr. Angelique Whitehurst Reader: Dr. David Siderovski Reader: Dr. Channing Der Reader: Dr. Pilar Blancafort Reader: Dr. Mohanish Deshmukh ABSTRACT KATHRYN CAPPELL: Symplekin and Transforming Acidic Coiled-Coil Containing Protein 3 Support the Cancer Cell Mitotic Spindle (Under the direction of Dr. Angelique Whitehurst) An increased rate of proliferation in cancer cells, combined with abnormalities in spindle architecture, places tumors under increased mitotic stress. Previously, our laboratory performed a genome-wide paclitaxel chemosensitizer screen to identify genes whose depletion sensitizes non- small cell lung cancer (NSCLC) cells to mitotic stress induced by paclitaxel treatment. This screen uncovered a cohort of genes that are required for viability only in the presence of paclitaxel. Two genes uncovered in this screen were the polyadenylation scaffold symplekin and the gametogenic protein transforming acidic coiled-coil containing protein 3 (TACC3). Herein, we examine the impact of polyadenylation and gametogenesis on the tumor cell mitotic spindle. First, we demonstrate that depletion of SYMPK and other polyadenylation components sensitizes many NSCLC cells, but not normal immortalized lines, to paclitaxel by inducing mitotic errors and leading to abnormal mitotic progression. Second, we demonstrate that multiple gametogenic genes are required for normal microtubule dynamics and mitotic spindle formation in the presence of paclitaxel.
  • Centrosome Impairment Causes DNA Replication Stress Through MLK3

    Centrosome Impairment Causes DNA Replication Stress Through MLK3

    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.09.898684; this version posted January 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation Zainab Tayeh 1, Kim Stegmann 1, Antonia Kleeberg 1, Mascha Friedrich 1, Josephine Ann Mun Yee Choo 1, Bernd Wollnik 2, and Matthias Dobbelstein 1* 1) Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany 2) Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany *Lead Contact. Correspondence and requests for materials should be addressed to M. D. (e-mail: [email protected]; ORCID 0000-0001-5052-3967) Running title: Centrosome integrity supports DNA replication Key words: Centrosome, CEP152, CCP110, SASS6, CEP152, Polo-like kinase 4 (PLK4), DNA replication, DNA fiber assays, R-loops, MLK3, MK2 alias MAPKAPK2, Seckel syndrome, microcephaly. Highlights: • Centrosome defects cause replication stress independent of mitosis. • MLK3, p38 and MK2 (alias MAPKAPK2) are signalling between centrosome defects and DNA replication stress through R-loop formation. • Patient-derived cells with defective centrosomes display replication stress, whereas inhibition of MK2 restores their DNA replication fork progression and proliferation. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.09.898684; this version posted January 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
  • Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant

    Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant

    Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7,
  • Tissue-Specific Splicing of a Ubiquitously Expressed Transcription Factor Is Essential for Muscle Differentiation

    Tissue-Specific Splicing of a Ubiquitously Expressed Transcription Factor Is Essential for Muscle Differentiation

    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation Soji Sebastian,1 Herve´ Faralli,1,4 Zizhen Yao,2,4 Patricia Rakopoulos,1,3 Carmen Palii,1 Yi Cao,2 Kulwant Singh,1 Qi-Cai Liu,1 Alphonse Chu,1 Arif Aziz,1 Marjorie Brand,1,3 Stephen J. Tapscott,2 and F. Jeffrey Dilworth1,3,5 1Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada,; 2Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; 3Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada Alternate splicing contributes extensively to cellular complexity by generating protein isoforms with divergent functions. However, the role of alternate isoforms in development remains poorly understood. Mef2 transcription factors are essential transducers of cell signaling that modulate differentiation of many cell types. Among Mef2 family members, Mef2D is unique, as it undergoes tissue-specific splicing to generate a muscle-specific isoform. Since the ubiquitously expressed (Mef2Da1) and muscle-specific (Mef2Da2) isoforms of Mef2D are both expressed in muscle, we examined the relative contribution of each Mef2D isoform to differentiation. Using both in vitro and in vivo models, we demonstrate that Mef2D isoforms act antagonistically to modulate differentiation. While chromatin immunoprecipitation (ChIP) sequencing analysis shows that the Mef2D isoforms bind an overlapping set of genes, only Mef2Da2 activates late muscle transcription. Mechanistically, the differential ability of Mef2D isoforms to activate transcription depends on their susceptibility to phosphorylation by protein kinase A (PKA).
  • Supplementary Material and Methods

    Supplementary Material and Methods

    Supplementary material and methods Generation of cultured human epidermal sheets Normal human epidermal keratinocytes were isolated from human breast skin. Keratinocytes were grown on a feeder layer of irradiated human fibroblasts pre-seeded at 4000 cells /cm² in keratinocyte culture medium (KCM) containing a mix of 3:1 DMEM and HAM’s F12 (Invitrogen, Carlsbad, USA), supplemented with 10% FCS, 10ng/ml epidermal growth factor (EGF; R&D systems, Minneapolis, MN, USA), 0.12 IU/ml insulin (Lilly, Saint- Cloud, France), 0.4 mg/ml hydrocortisone (UpJohn, St Quentin en Yvelelines, France) , 5 mg/ml triiodo-L- thyronine (Sigma, St Quentin Fallavier, France), 24.3 mg/ml adenine (Sigma), isoproterenol (Isuprel, Hospira France, Meudon, France) and antibiotics (20 mg/ml gentamicin (Phanpharma, Fougères, France), 100 IU/ml penicillin (Phanpharma), and 1 mg/ml amphotericin B (Phanpharma)). The medium was changed every two days. NHEK were then cultured over a period of 13 days according to the protocol currently used at the Bank of Tissues and Cells for the generation of clinical grade epidermal sheets used for the treatment of severe extended burns (Ref). When needed, cells were harvested with trypsin-EDTA 0.05% (Thermo Fisher Scientific, Waltham, MA, USA) and collected for analysis. Clonogenic assay Keratinocytes were seeded on a feeder layer of irradiated fibroblasts, at a clonal density of 10-20 cells/cm² and cultivated for 10 to 14 days. Three flasks per tested condition were fixed and colored in a single 30 mns step using rhodamine B (Sigma) diluted at 0.01 g/ml in 4% paraformaldehyde. In each tested condition, cells from 3 other flasks were numerated after detachment by trypsin treatment.