The Human Blueprint - Multiple Genetic Software Codes for Life

The complex non-coding elements in the human genome serve to inform epigenetic/histone codes, enhancer codes, and 3D folding codes! The multiple codes show deep function in what used to be thought of as “junk DNA” because it doesn’t code for proteins.

Nuclear organization and gene regulation in 3D

The massively complex human genome is a super-computer that carefully controls it’s information. It uses chemical-genetic circuits, 3D folding, and signal integration to maintain cell identity and all biological functions. Our lab is excited to unravel the principles of the super-computer we call the epigenome.

Areas of innovation: Systems biology, bioinformatics, computational biology, machine learning, novel wet-lab technology.

Chemistry targeting transcription in cancer

Cancer can’t live without transcribing its favorite oncogenes, especially those at the highest expression levels that are also cancer-type-specific. Genetic CRISPR screening has highlighted that many excellent targets for killing cancer cells are the proteins needed for high-level transcription (ie, BRD4, CBP/p300, MYC). We are designing new chemical approaches to drugging transcription selectively, and giving mechanistic credentials to new ways of hitting cancer where it hurts.

Areas of innovation: Chemical biology, medicinal chemistry.

Phase separation and nuclear condensate formation

The idea that proteins congregate into “droplets”, like oil in water, to concentrate their collective activity at a specific location in the epigenome, is quite fascinating. Since so much of the epigenome machinery is devoted to molecular recognition of either DNA sequence (transcription factors) or to recognition of post-translational modifications (“epi-marks” like H3K27ac), our lab is intrigued to investigate how these “friend-finder” capacities lead to the formation and function of nuclear condensates at active genes.

Areas of innovation: nuclear condensate biology, transcriptional control, post-translational modification of transcription factors and transcriptional co-activators.

Our new lab has several top-secret projects in these topic areas, and if you’re interested in joining our team we can give you security clearance!

Cancers we aim to cure

In addition to being motivated by the sheer beauty of biology (yes, even when studied in something as ugly as cancer), we’re also inspired by the tireless efforts of the patients, doctors, family members and friends that battle cancer. We believe that the deeper we understand epigenetics and gene control, the better we will be at developing new ammo in the war against cancer. Our lab is currently testing new epigenetic therapies for:

1. Childhood Cancers, especially Rhabdomyosarcoma

2. Lethal forms of Prostate Cancer

We patent new molecular strategies to cure these cancers, and test them in the most disease-relevant models. We also work with teams of medical doctors and chemists across multiple institutions, and aim to take our most exciting molecules into the clinic.

For a full list of our work, visit Google Scholar

(you can also find the PDFs of our work in this folder)

Y. Asante, K. Benischke, I. Osman, Q.A. Ngo, J. Wurth, D. Laubscher, H. Kim, B. Udhayakumar, M.I.H. Khan, D.H. Chin, J. Porch, M. Chakraborty, R. Sallari, O. Delattre, S. Zaidi, S. Morice, D. Surdez, S.G. Danielli, B.W. Schäfer, B.E. Gryder*, & M. Wachtel*. PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution. Nature Communications, 2023, *co-corresponding authors

D.H. Chin, I. Osman, J. Porch, H. Kim, K.K. Buck, J. Rodriguez, B. Carapia, D. Yan, S.B. Moura, J. Sperry, J. Nakashima, K. Altman, D. Altman, & B.E. Gryder. BET Bromodomain Degradation Disrupts Function but Not 3D Formation of RNA Pol2 Clusters. Pharmaceuticals, 2023

D. Laubscher^†, B.E. Gryder^†, B.D. Sunkel^†, T. Andresson, M. Wachtel, S. Das, B. Roschitzki, W. Wolski, X.S. Wu, H.-C. Chou, Y.K. Song, C. Wang, J.S. Wei, M. Wang, X. Wen, Q.A. Ngo, J.G. Marques, C.R. Vakoc, B.W. Schäfer, B.Z. Stanton, & J. Khan. BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma. Nature Communications, 2021, ^†co-first authors

A. M. Garzón-Porras, E. Chory, B. E. Gryder, Dynamic Opposition of Histone Modifications, ACS Chemical Biology, 2022

C. F. Hays and B. E. Gryder, Epigenetic convergence in the rising tide of opioid overdose deaths, Molecular Psychiatry 2022

Corradin, Sallari, Hoang, Kassim, Ben Hutta, Cuoto, Quach, Lovrenert, Hays, Gryder et al., Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid overdose. Molecular Psychiatry, 2022

B.E. Gryder*, P.C. Scacheri, T. Ried* & J. Khan*. Chromatin Mechanisms Driving Cancer. Cold Spring Harb Perspect Biol, 2021. *co-corresponding

S. Pomella^†, P. Sreenivas^†, B.E. Gryder^†, et. al., J. Khan*, R. Rota*, M. S. Ignatius*. Interaction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma. Nature Comm., 2021^†co-first authors,^*co-corresponding authors

D. Banerjee*, B.E. Gryder* et al., C. Thiele*, Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation. BioRxiv, 2020 *co-corresponding authors

B.E. Gryder*, M. Wachtel, K. Chang, O. El Demerdash, N. G. Aboreden, W. Ewert, S. Pomella, W. Mohammed, R. Rota, J. S. Wei, Y. Song, B. Schaefer, C. R. Vakoc, J. Khan*. Miswired Enhancer Logic Drives a Cancer of the Muscle Lineage. iScience, 2020 *co-corresponding authors (chosen for the journal’s cover artwork, June 26, 2020 issue)

B.E. Gryder*, J. Khan*, B.Z. Stanton*. Absolute Quantification of Architecture (AQuA-HiChIP) Enables Measurement of Differential Chromatin Interactions. Nature Protocols, 2020 *co-corresponding authors

J. G. Marques, B.E. Gryder et al., NuRD subunit CHD4 regulates super-enhancer accessibility in Rhabdomyosarcoma and represents a general tumor dependency. eLife, 2020

N. C. Whitlock, et al. B.E. Gryder, Capaldo, B., Ye, H., Sowalsky, A., MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity. Oncogene, 2020.

R. Adelaiye-Ogala, B.E. Gryder, et al., D. VanderWeele, Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor. Mol. Cancer Ther., 2020.

B.E. Gryder*, S. Pomella, et. al., J. Khan*. Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma. Nature Genetics, 2019 *co-corresponding authors

A.M. Chiarella, K.V. Butler, B.E. Gryder, D. Lu, T.A. Wang, X. Yu, S. Pomella, J. Khan, J. Jin, N.A. Hathaway. Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery. Nature Biotechnology, 2019

B.E. Gryder^†, L. Wu^† et. al., J. Qi*, J. Khan*. Chemical genomics reveals histone deacetylases are required for core regulatory transcription. Nature Communications, 2019 ^†co-first authors,*co-corresponding authors

M.E. Yohe^†, B.E. Gryder^†, et. al., C. Thomas, J. Khan. MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Science Translational Medicine, 2018 ^†co-first authors

B.E. Gryder, M.E. Yohe, H.-C. Chou, et. al., K. Zhao, C.J. Thomas, J. Khan. PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer Discovery, 2017

B.E. Gryder, Nelson C, and Shepard S, Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer. Entropy. 2013; 15(1):234-261.

Research