Breadcrumb

Gordon L. Hager, Ph.D.

Gordon L. Hager, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute

RESEARCH SUMMARY

Reorganization of the nuclear chromatin environment is a fundamental component of gene regulation. A primary focus of our work is the identification and characterization of activities that are involved in chromatin modification, and characterization of the mechanisms by which these modifications and transitions are orchestrated into the final effects of gene activation, repression, and epigenetic inheritance. We are also interested in how these activities function in the context of the living cell nucleus, and the large-scale reorganization of nucleoprotein structure that accompanies many regulatory processes. We have studied nuclear receptors as important models in understanding chromatin modification and restructuring.

Areas of Expertise

1) gene regulation, 2) transcription factor dynamics, 3) chromatin structure and function,
4) real time imaging, 5) epigenetics and cancer

Publications

Selected Key Publications

Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model.

Garcia, DA, Fettweis, G, Presman, DM, Paakinaho, V, Jarzynski, C, Upadhyaya, A, and Hager GL
Nucleic Acids Research. 49: 6605-6620, 2021.
Full-Text Article
[ Journal Article ]

An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors

Garcia, DA, Johnson, TA, Presman, DM, Fettweis, G, Wagh, K, Rinaldi, L, Stavreva, DA, Paakinaho, V, Jensen, RAM, Mandrup, S, Upadhyaya A, Hager GL.
Molecular Cell. 81(7): 1484-1498.e6, 2021.
Full-Text Article
[ Journal Article ]

Transcriptional Bursting and Co-bursting Regulation by Steroid Hormone Release Pattern and Transcription Factor Mobility

Stavreva DA, Garcia DA, Fettweis G, Gudla PR, Zaki GF, Soni V, McGowan A, Williams G, Huynh A, Palangat M, Schiltz RL, Johnson TA, Presman DM, Ferguson ML, Pegoraro G, Upadhyaya A, Hager GL.
Mol Cell. 75(6): 1161-77, 2019. [ Journal Article ]

Glucocorticoid receptor quaternary structure drives chromatin occupancy and transcriptional outcome

Paakinaho V, Johnson TA, Presman DM, Hager GL.
Genome Res. 29(8): 1223-34, 2019. [ Journal Article ]

Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions

Swinstead EE, Miranda TB, Paakinaho V, Baek S, Goldstein I, Hawkins M, Karpova TS, Ball D, Mazza D, Lavis LD, Grimm JB, Morisaki T, Grøntved L, Presman DM, Hager GL.
Cell. 165(3): 593-605, 2016. [ Journal Article ]

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Covers

A Transcription factor (TF) must engage with chromatin to regulate gene expression. Using single-molecule tracking, it is possible to follow individual TF molecules inside live cells. The image illustrates how a TF (shown as a car) travels through a rugged energy landscape of binding affinities arising from the heterogeneity of the nuclear microenvironment and binding sites, giving rise to a power-law distribution of residence times.

Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model

Published Date

Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs—one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multi-exponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.

Citation

Nucleic Acids Research, Volume 49, Issue 12, 9 July 2021, Pages 6605–6620, https://doi.org/10.1093/nar/gkab072