Email

nicolas.young@bcm.edu

Positions

Associate Professor

Biochemistry & Molecular Biology
Baylor College of Medicine
Houston, TX US

Associate Professor

Center for Precision Environmental Health
Baylor College of Medicine
Houston, TX USA

Assistant Professor

Department of Molecular and Cellular Biology
Baylor College of Medicine
Houston, TX

Faculty Senator

Baylor College of Medicine
Houston, TX

Faculty Member & Recruitment Chair

Graduate Program in Chemical, Physical, Structural Biology
Baylor College of Medicine

Faculty Member

Graduate Program in Cancer & Cell Biology
Baylor College of Medicine

Addresses

BCM-Taub Building (Office)

Room: T338C
Houston, TX 77030
United States

Education

Postdoctoral Fellowship at Princeton University

Princeton, New Jersey United States

Molecular Biology

PhD from University of California, Davis

Davis, California United States

Bioanalytical Chemistry

BS from University of California, Berkeley

Berkeley, California United States

Chemistry

Professional Interests

• Top Down Proteomics
• Post-translational Modifications
• Chromatin
• Epigenetics
• Nuclear Receptors
• Cancer
• Biochemistry
• Histones
• Transcription
• Transcription Factors
• Chromosomes, Chromatin And DNA Biology

Professional Statement

A primary thesis underlying all of the work in the Young lab is that multiple PTMs function in concert on single molecules (proteoforms) to encode complex information. This may be considered analogous to a bar code. A natural outcome of this mechanism is the integration of diverse signals. Signals transduced through individual PTMs may be subjected to logical operations and orders of magnitude more information may be persistently stored in a combinatorial register. Such a mechanism of signal integration is widely considered necessary. Although most work to date has explored PTMs for function on a site-by-site basis, strong evidence of connections, interplay, and dependencies abound between PTMs and some combinatorial molecular mechanisms have been demonstrated. Strong evidence supports the concept that histones and other densely modified proteins such as ER, work to store and transduce information combinatorially at the proteoform level. For example, clinical studies of cancer epigenetics show exceptional prognostic/diagnostic value only when multiple PTMs are linked ex post facto. Importantly, it is the pattern of several histone modifications that is able to accurately distinguish outcome.

Definition: A proteoform is a single molecular species resulting from the specific set of modifications (PTMs, splicesomal or proteolytic processing, etc.) to the protein that coexist on one single molecule.

Thus, proteoform level information that connects multiple PTMs on single molecules will be even more predictive and informative of useful combination therapy strategies. The FDA now recognizes that combination therapies may function irrespective of independent efficacy. Thus, addressing the questions in this proposal from a proteoform perspective will solve outstanding contradictions with respect to the currently annotated biological function of isolated PTMs and result in advances in our understanding of and ability to modulate the chromatin-based gene regulatory system, by studying players such as histones, nuclear receptors (such as estrogen and progesterone receptors) and cancer linked transcription factors (such as Myc). These targets are all central players in Epigenetics (chromatin regulation) that control transcription regulation, stem cell biology, regenerative medicine, cancer biology, and fundamental cellular physiology. In order to innovate the study of these critical systems we work at the interface of bioanalytical mass spectrometry, molecular biology/biochemistry, epigenetics, and systems biology. These are combined in an effort to elucidate the role of protein post-translational modifications in the regulation, decision-making, and epigenetic memory of eukaryotes. We use cutting edge analytical tools such as top down mass spectrometry, novel chromatography, and computational methods to study otherwise inaccessible aspects of biology. For example such novel subjects include: 1) How multiple post-translational modifications on single protein molecules function in concert and 2) the role of un- or understudied protein variants in gene regulation and disease mechanisms.

Websites

Selected Publications

• Wang T, Holt MV, Young NL "The histone H4 proteoform dynamics in response to SUV4-20 inhibition reveals single molecule mechanisms of inhibitor resistance." Epigenetics Chromatin. 2018 Jun 7;11(1) Pubmed PMID: 29880017
• Voigt P, LeRoy G, Drury WJ 3rd, Zee BM, Son J, Beck DB, Young NL, Garcia BA, Reinberg D "Asymmetrically modified nucleosomes." Cell. 2012 Sep; Pubmed PMID: 23021224
• Young NL, DiMaggio PA, Plazas-Mayorca MD, Baliban RC, Floudas CA, Garcia BA "High throughput characterization of combinatorial histone codes." Mol Cell Proteomics. 2009 Oct; Pubmed PMID: 19654425
• Chen Y, Hoover ME, Dang X, Shomo AA, Guan X1, Marshall AG, Freitas MA, Young NL "Quantitative Mass Spectrometry Reveals that Intact Histone H1 Phosphorylations are Variant Specific and Exhibit Single Molecule Hierarchical Dependence." Mol Cell Proteomics. 2015 Jul; Pubmed PMID: 26209608