Overview: Biochemist and neurobiologist interested in uncovering the molecular basis of human disorders and disease. Currently performing postdoctoral research at Stanford University investigating the impact of chromatin regulatory processes in neurodevelopment.

Research Interests: Freddy Valencia graduated with a PhD in Chemical Biology at Harvard and is currently a Science Fellow at Stanford University. His long-term research interests aim to uncover the underlying epigenetic mechanisms implicated in the development of human disorders and diseases. In Dr. Cigall Kadoch's laboratory at the Dana-Farber Cancer Institute, his work examined the biochemical, structural, and functional consequences that perturbations to the mammalian SWI/SNF (mSWI/SNF or BAF) chromatin-remodeling complex have in the cell. More precisly, his research has examined the molecular mechanisms through which SMARCB1 mutations are implicated in cancer and neurodevelopmental disorders and contributed to the characterization of the modular organization of the mSWI/SNF protein complexes.

Higher Education Advocacy: Born and raised in Santa Ana, California to parents who immigrated from Mexico, Freddy is passionate about teaching and mentoring students from underrepresented groups in the sciences. Through his involvement in programs like Breakthrough Collaborative while in high school, Tutors for a Cause while at Pitzer College, and Dana-Farber?s Science Enrichment Program at Harvard University, he aims to serve as a mentor, role model, and agent of change for underrepresented minority students in their pursuit of higher education. During his graduate studies, Freddy was elected as Co-President of the Minority Biomedical Scientists of Harvard (MBSH) student organization and was one of two inaugural Diversity and Inclusion Fellows for Harvard University's Graduate School of Arts and Sciences. Through these roles, he worked to foster collaboration and a sense of community between students of color throughout the Harvard Community.

Honors & Awards

  • Stanford Science Fellow, Stanford University (2020)
  • Diversity and Inclusion Fellow, Harvard Graduate School of Arts and Sciences (2018-2019)
  • Ford Foundation Predoctoral Fellowship, National Academies of Sciences, Engineering, and Medicine (2017-2020)
  • HHMI Gilliam Fellowship, Howard Hughes Medical Institute (HHMI) (2017-2020)
  • Graduate Prize Fellowship, Harvard University (2014-2017)
  • HHMI Summer Undergraduate Research Fellow, HHMI, The Claremont Colleges (2013)
  • McNair Scholar, Ronald E. McNair Postbaccalaureate Achievement Program, Claremont Graduate University (2012)
  • A Better Chance Scholar, A Better Chance (2006-2010)

Professional Education

  • Doctor of Philosophy, Harvard University (2020)
  • Bachelor of Arts, Pitzer College (2014)

Stanford Advisors


All Publications

  • The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma. Nature structural & molecular biology McBride, M. J., Mashtalir, N., Winter, E. B., Dao, H. T., Filipovski, M., D'Avino, A. R., Seo, H. S., Umbreit, N. T., St Pierre, R., Valencia, A. M., Qian, K., Zullow, H. J., Jaffe, J. D., Dhe-Paganon, S., Muir, T. W., Kadoch, C. 2020; 27 (9): 836?45


    Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma-specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.

    View details for DOI 10.1038/s41594-020-0466-9

    View details for PubMedID 32747783

  • Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling. Cell Valencia, A. M., Collings, C. K., Dao, H. T., St Pierre, R., Cheng, Y. C., Huang, J., Sun, Z. Y., Seo, H. S., Mashtalir, N., Comstock, D. E., Bolonduro, O., Vangos, N. E., Yeoh, Z. C., Dornon, M. K., Hermawan, C., Barrett, L., Dhe-Paganon, S., Woolf, C. J., Muir, T. W., Kadoch, C. 2019; 179 (6): 1342?56.e23


    Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic ? helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.

    View details for DOI 10.1016/j.cell.2019.10.044

    View details for PubMedID 31759698

    View details for PubMedCentralID PMC7175411

  • Chromatin regulatory mechanisms and therapeutic opportunities in cancer. Nature cell biology Valencia, A. M., Kadoch, C. 2019; 21 (2): 152?61


    Research over the past several decades has unmasked a major contribution of disrupted chromatin regulatory processes to human disease, particularly cancer. Advances in genome-wide technologies have highlighted frequent mutations in genes encoding chromatin-associated proteins, identified unexpected synthetic lethal opportunities and enabled increasingly comprehensive structural and functional dissection. Here, we review recent progress in our understanding of oncogenic mechanisms at each level of chromatin organization and regulation, and discuss new strategies towards therapeutic intervention.

    View details for DOI 10.1038/s41556-018-0258-1

    View details for PubMedID 30602726

    View details for PubMedCentralID PMC6755910

  • A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation NATURE CELL BIOLOGY Michel, B. C., D'Avino, A. R., Cassel, S. H., Mashtalir, N., McKenzie, Z. M., McBride, M. J., Valencia, A. M., Zhou, Q., Bocker, M., Soares, L. M., Pan, J., Remillard, D. I., Lareau, C. A., Zullow, H. J., Fortoul, N., Gray, N. S., Bradner, J. E., Chan, H., Kadoch, C. 2018; 20 (12): 1410-+


    Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.

    View details for DOI 10.1038/s41556-018-0221-1

    View details for Web of Science ID 000451328500013

    View details for PubMedID 30397315

    View details for PubMedCentralID PMC6698386

  • Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell Mashtalir, N., D'Avino, A. R., Michel, B. C., Luo, J., Pan, J., Otto, J. E., Zullow, H. J., McKenzie, Z. M., Kubiak, R. L., St Pierre, R., Valencia, A. M., Poynter, S. J., Cassel, S. H., Ranish, J. A., Kadoch, C. 2018; 175 (5): 1272?88.e20


    Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes are multi-subunit molecular machines that play vital roles in regulating genomic architecture and are frequently disrupted in human cancer and developmental disorders. To date, the modular organization and pathways of assembly of these chromatin regulators remain unknown, presenting a major barrier to structural and functional determination. Here, we elucidate the architecture and assembly pathway across three classes of mSWI/SNF complexes-canonical BRG1/BRM-associated factor (BAF), polybromo-associated BAF (PBAF), and newly defined ncBAF complexes-and define the requirement of each subunit for complex formation and stability. Using affinity purification of endogenous complexes from mammalian and Drosophila cells coupled with cross-linking mass spectrometry (CX-MS) and mutagenesis, we uncover three distinct and evolutionarily conserved modules, their organization, and the temporal incorporation of these modules into each complete mSWI/SNF complex class. Finally, we map human disease-associated mutations within subunits and modules, defining specific topological regions that are affected upon subunit perturbation.

    View details for DOI 10.1016/j.cell.2018.09.032

    View details for PubMedID 30343899

    View details for PubMedCentralID PMC6791824

  • SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nature genetics Nakayama, R. T., Pulice, J. L., Valencia, A. M., McBride, M. J., McKenzie, Z. M., Gillespie, M. A., Ku, W. L., Teng, M., Cui, K., Williams, R. T., Cassel, S. H., Qing, H., Widmer, C. J., Demetri, G. D., Irizarry, R. A., Zhao, K., Ranish, J. A., Kadoch, C. 2017; 49 (11): 1613?23


    Perturbations to mammalian SWI/SNF (mSWI/SNF or BAF) complexes contribute to more than 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor, an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in complex assembly or integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of Polycomb-mediated repression at bivalent promoters. We demonstrate differential regulation by two distinct mSWI/SNF assemblies, BAF and PBAF complexes, enhancers and promoters, respectively, suggesting that each complex has distinct functions that are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are co-opted or abated to drive human cancers and developmental disorders.

    View details for DOI 10.1038/ng.3958

    View details for PubMedID 28945250

    View details for PubMedCentralID PMC5803080

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