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6. Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network.

Author

Mukherjee, Shreyasi, Chaturvedi, Praneet, Rankin, Scott A, Fish, Margaret B, Wlizla, Marcin, Paraiso, Kitt D, MacDonald, Melissa, Chen, Xiaoting, Weirauch, Matthew T, Blitz, Ira L, Cho, Ken Wy, and Zorn, Aaron M

Subjects
Wnt, beta-catenin, developmental biology, endoderm, enhancers, sox17, transcription, xenopus, Biochemistry and Cell Biology
Abstract

Lineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN in Xenopus gastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription apparently independent of Tcfs, whereas on other enhancers, Sox17 represses β-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/β-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and β-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.

Published
2020

20. Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium

Author

Fuller, Mark T., primary, Dadoo, Omid, additional, Xiong, Ting, additional, Chivukula, Pardh, additional, MacDonald, Melissa E., additional, Lee, Samuel K., additional, Austin, Richard C., additional, Igdoura, Suleiman A., additional, and Trigatti, Bernardo L., additional

Published
2023
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21. Additional file 1 of A therapeutic target for CKD: activin A facilitates TGFβ1 profibrotic signaling

Author

Soomro, Asfia, Khajehei, Mohammad, Li, Renzhong, O’Neil, Kian, Zhang, Dan, Gao, Bo, MacDonald, Melissa, Kakoki, Masao, and Krepinsky, Joan C.

Abstract

Additional file 1: Figure S1. Follistatin does not inhibit early Smad3 activation by TGFβ1. MC were treated with follistatin for 30 min prior to the addition of TGFβ1 for 30 min. Smad3 phosphorylation was assessed by immunoblotting. ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S2. Activin A supports TGFβ1 profibrotic effects in renal fibroblasts. Follistatin (FST) and actA neutralization attenuated TGFβ1-induced fibronectin (FN), α-smooth muscle actin (αSMA) and connective tissue growth factor (CTGF) upregulation as well as Smad3 activation at 48 h (n = 5–8). *, **, ***, ****P < 0.05, 0.01, 0.001, 0.000; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S3. Confirmation of specificity of the actA neutralizing antibody in MC. The neutralizing antibody for actA prevents actA, but not actB, induction of Smad3 transcriptional activity at 24 h as assessed by the CAGA12 luciferase reporter (n = 6). **, ****P < 0.01, 0.0001; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S4. ActA inhibition prevents profibrotic gene upregulation by TGFβ1 in MC. Increased fibronectin (FN), collagen Iα1 (ColI) and α-smooth muscle actin (αSMA) transcripts by 24 h of TGFβ1 were attenuated with a neutralizing actA antibody (n = 6). **, ***P < 0.01, 0.001; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S5. ActA enables renal fibroblast proliferation, migration and gel contraction. (a) Increased cell proliferation induced by TGFβ1 (24 h) is significantly decreased by both follistatin and a neutralizing actA antibody (n = 3). (b) TGFβ1 increased wound closure after 24 h in a scratch assay. This was inhibited by both follistatin and an actA neutralizing antibody (n = 3). (c) TGFβ1 induced collagen gel contraction after 72 h, which was prevented by follistatin and an actA neutralizing antibody (n = 3). *, **P < 0.05, 0.01; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S6. TGFβ1 induces activin A, but not activin B production in human proximal tubular cells. TGFβ1: (a) upregulates actA, but not actB, transcript levels at 24 h (n = 6–9); (b) induces actA secretion in a dose-dependant manner (0.5–5 ng/ml TGFβ1) (n = 3); (c) has no effect on actB secretion at 24 h (n = 3). **, ***, ****P < 0.01, 0.001, 0.0001; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S7. TGFβ3 induces actA synthesis and secretion in MC. ELISA shows a small increase in both a) actA secretion into the medium (n = 3) and b) cellular actA levels in response to 24 h of TGFβ3 treatment (n = 3). **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S8. In MC, 24 h TGFβ1 increases transcript levels for activin type I and II receptors ALK4 and ActRIIA/B respectively. This is dependent on activin signaling itself as it is inhibited by follistatin (n = 3). *, **, ***P < 0.05, 0.01, 0.001; one-way ANOVA with Tukey’s multiple comparisons post hoc test. Figure S9. ActA does not regulate the activation of Smad2 by TGFβ1 in MC. Smad2 activation was assessed by its phosphorylation after 24 h of TGFβ1. Neither follistatin nor the actA neutralizing antibody prevented its activation (n = 3); one-way ANOVA with Tukey’s multiple comparisons post hoc test.

Published
2023
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22. Inhibitory Antibodies against PCSK9 Reduce Surface CD36 and Mitigate Diet-Induced Renal Lipotoxicity

Author

Byun, Jae Hyun, primary, Lebeau, Paul F., additional, Platko, Khrystyna, additional, Carlisle, Rachel E., additional, Faiyaz, Mahi, additional, Chen, Jack, additional, MacDonald, Melissa E., additional, Makda, Yumna, additional, Yousof, Tamana, additional, Lynn, Edward G., additional, Dickhout, Jeffrey G., additional, Krepinsky, Joan C., additional, Weaver, Fiona, additional, Igdoura, Suleiman A., additional, Seidah, Nabil G., additional, and Austin, Richard C., additional

Published
2022
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28. LETTERS

Author

Sorensen, Randy, Caldwell, Kenneth, Kent, Fred, Schafers, Neal, Clement, Laurence A., Ward, Janet, Krahmer, Ana, Mueller, Jon, MacDonald, Melissa, Weiss, Glenn, and O'Connell, Michael

Published
2007

29. Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network

Author

Mukherjee, Shreyasi, primary, Chaturvedi, Praneet, additional, Rankin, Scott A, additional, Fish, Margaret B, additional, Wlizla, Marcin, additional, Paraiso, Kitt D, additional, MacDonald, Melissa, additional, Chen, Xiaoting, additional, Weirauch, Matthew T, additional, Blitz, Ira L, additional, Cho, Ken WY, additional, and Zorn, Aaron M, additional

Published
2020
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30. Author response: Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endoderm gene regulatory network

Author

Mukherjee, Shreyasi, primary, Chaturvedi, Praneet, additional, Rankin, Scott A, additional, Fish, Margaret B, additional, Wlizla, Marcin, additional, Paraiso, Kitt D, additional, MacDonald, Melissa, additional, Chen, Xiaoting, additional, Weirauch, Matthew T, additional, Blitz, Ira L, additional, Cho, Ken WY, additional, and Zorn, Aaron M, additional

Published
2020
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31. Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles

Author

Camps, Jordi, primary, Breuls, Natacha, additional, Sifrim, Alejandro, additional, Giarratana, Nefele, additional, Corvelyn, Marlies, additional, Danti, Laura, additional, Grosemans, Hanne, additional, Vanuytven, Sebastiaan, additional, Thiry, Irina, additional, Belicchi, Marzia, additional, Meregalli, Mirella, additional, Platko, Khrystyna, additional, MacDonald, Melissa E., additional, Austin, Richard C., additional, Gijsbers, Rik, additional, Cossu, Giulio, additional, Torrente, Yvan, additional, Voet, Thierry, additional, and Sampaolesi, Maurilio, additional

Published
2020
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40. Development and evaluation of an instrument for the critical appraisal of randomized controlled trials of natural products

Author

Whelan Anne, Jurgens Tannis, MacDonald Melissa, and Lord Lindsay

Subjects
Other systems of medicine, RZ201-999
Abstract

Abstract Background The efficacy of natural products (NPs) is being evaluated using randomized controlled trials (RCTs) with increasing frequency, yet a search of the literature did not identify a widely accepted critical appraisal instrument developed specifically for use with NPs. The purpose of this project was to develop and evaluate a critical appraisal instrument that is sufficiently rigorous to be used in evaluating RCTs of conventional medicines, and also has a section specific for use with single entity NPs, including herbs and natural sourced chemicals. Methods Three phases of the project included: 1) using experts and a Delphi process to reach consensus on a list of items essential in describing the identity of an NP; 2) compiling a list of non-NP items important for evaluating the quality of an RCT using systematic review methodology to identify published instruments and then compiling item categories that were part of a validated instrument and/or had empirical evidence to support their inclusion and 3) conducting a field test to compare the new instrument to a published instrument for usefulness in evaluating the quality of 3 RCTs of a NP and in applying results to practice. Results Two Delphi rounds resulted in a list of 15 items essential in describing NPs. Seventeen item categories fitting inclusion criteria were identified from published instruments for conventional medicines. The new assessment instrument was assembled based on content of the two lists and the addition of a Reviewer's Conclusion section. The field test of the new instrument showed good criterion validity. Participants found it useful in translating evidence from RCTs to practice. Conclusion A new instrument for the critical appraisal of RCTs of NPs was developed and tested. The instrument is distinct from other available assessment instruments for RCTs of NPs in its systematic development and validation. The instrument is ready to be used by pharmacy students, health care practitioners and academics and will continue to be refined as required.

Published
2009
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42. In the consumer's court

Author

MacDonald, Melissa

Subjects
Food additives industry -- Management, Advertising, marketing and public relations, Business, Chemicals, plastics and rubber industries, Nutrition Labeling and Education Act of 1990
Abstract

Trends in the food additives industry are described. Most significant is the implementation of the Nutritional Labeling and Education Act of 1990, which requires the presentation of more comprehensive labelling on food products. There are both positive and negative marketing aspects to the law, and the effect on consumers is yet to be determined. Other issues include the pressure to keep prices low due to competition from private label products. Quality, meanwhile is rising. The flavors industry, at $67 million in sales, is the fastest growing sector of the food additives industry, increasing at 6% annually.

Published
1994

47. An Organocatalytic Tethering Strategy: Aldehyde-Catalyzed Cope-type Hydroaminations of Allylic Amines

Author

MacDonald, Melissa

Abstract

Intermolecular reactions have long been a challenge in organic chemistry due to their high negative entropy and difficult nature, which often includes achieving regioselectivity and stereoselectivity. One strategy that has showed promise in overcoming these obstacles is the use of stoichiometric tethers to effectively temporarily make the reaction an intramolecular system. Therefore in several steps, the formation of a temporary tether, performing the desired reaction, and removal of the tether can enable a selective intermolecular reaction. The clear drawbacks to this method are the several steps required for a single transformation, the inherent waste and reduced overall yield for the synthetic sequence. This work aims at creating a catalytic approach to tethering to by-pass the above limitations and showcase how small organic molecules are effective catalysts’ and can induce asymmetry simply via temporary intramolecularity. The first part of this thesis illustrates this organocatalytic tethering approach via the application of the Cope-type hydroamination of alkenes. The intermolecular reaction of this methodology is extremely difficult and the goal of this work was to create a solution for the harsh conditions and low yields. This chapter describes a proof of concept for our approach using allylic amines and hydroxylamines, and a preliminary look at an asymmetric version of this reaction. The second part of this thesis describes a mechanistic study of our catalytic cycle and provides a detailed look at inhibition and off-cycle pathways. Through this research a second-generation catalyst, formaldehyde, was discovered and an advanced scope is presented. II" The final portion of the thesis focuses on an enantioselective and diastereoselective Cope-type hydroamination of alkenes via the organocatalytic tethering strategy. Optimization and substrate scope are presented, along with a discussion of the origins of selectivity. Derivatization of the final products is explored and future applications of the strategy are discussed.

Published
2014
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