Andrew S. Belmont | School of Molecular & Cellular Biology

We are interested in how 10 and 30 nm chromatin fibers fold into interphase and mitotic chromosomes, how interphase chromosomes are moved and positioned within nuclei, and what this means for DNA functions such as transcription and replication. Currently, our understanding of these higher levels of chromatin organization, which we refer to as large-scale chromatin structure, is poor. We use a combination of molecular biology, cell biology, genetics, and microscopy to visualize nuclear positioning and folding dynamics of specific chromosome regions and individual gene loci and to relate this to regulation of transcription and replication.

We developed methods for tagging specific gene loci in live cells using operator repeats. We applied these methods, first using engineered chromosome regions and more recently using CRISPR-based approaches to introduce these tags at endogenous loci. These approaches allow us to study particular gene loci. Surprisingly, over the years we found that different large-scale chromatin compaction states are tightly correlated with differential positioning within the nucleus. Moreover, we observed directed, long-range interphase chromosome movements coupled to transcriptional activation.

Most recently, we have been using cycles of exploration using sequence-based genomic methods and microscopy to probe how genome position may be related to regulation of gene expression examining particular gene loci. Specifically, we developed TSA-seq to map genome-wide cytological distances of chromosome loci to specific nuclear compartments.

Our recent work has focused on the relationship between gene expression and nuclear genome positioning relative to nuclear speckles and other nuclear condensates that spatially correlate with nuclear speckles.

Education

A.B., Princeton University (Physics)
M.D./Ph.D., Temple University (Biophysics)
Postdoc., University of California-San Francisco

Additional Campus Affiliations

Center for Biophysics & Quantitative Biology

External Links

Complete publications list

Highlighted Publications

Representative Publications

Omid Gholamalamdari, Tom van Schaik, Yuchuan Wang, Pradeep Kumar, Liguo Zhang, Yang Zhang, Gabriela A Hernandez Gonzalez, Athanasios E Vouzas, Peiyao A Zhao, David M Gilbert, Jian Ma, Bas van Steensel, Andrew S Belmont (2024) Beyond A and B Compartments: how major nuclear locales define nuclear genome organization and function, eLife, 13:RP99116, https://doi.org/10.7554/eLife.99116.1

Pradeep Kumar, Omid Gholamalamdari, Yang Zhang, Liguo Zhang, Anastassiia Vertii, Tom van Schaik, Daan Peric-Hupkes, Takayo Sasaki, David M Gilbert, Bas van Steensel, Jian Ma, Paul D Kaufman, Andrew S Belmont, Nucleolus and centromere TSA-seq reveals variable localization of heterochromatin in different cell types, Communications Biology 7:1135 (2024) https://doi.org/10.1038/s42003-024-06838-7

Job Dekker^1,2,*, Frank Alber³, Sarah Aufmkolk⁴, Brian J. Beliveau⁵, Benoit G. Bruneau^6,12, Andrew Belmont⁷, Lacramioara Bintu⁸, Alistair Boettiger⁸, Riccardo Calandrelli⁹, Christine Disteche⁵, David M. Gilbert²², Thomas Gregor¹⁰, Anders S. Hansen¹¹, Bo Huang¹², Danwei Huangfu¹³, Reza Kalhor¹⁴, Christina Leslie¹³, Wenbo Li¹⁵, Yun Li¹⁶, Jian Ma¹⁷, William S. Noble⁵, Peter J. Park⁴, Jennifer E. Phillips-Cremins¹⁸, Katherine S. Pollard^6,12,23, Susanne Rafelski¹⁹, Bing Ren⁹, Yijun Ruan²⁰, Yaron Shav-Tal²¹, Yin Shen¹², Jay Shendure⁵, Xiaokun Shu¹², Caterina Strambio-De-Castillia¹, Anastassiia Vertii¹, Huaiying Zhang¹⁷, Sheng Zhong^9,,*, Spatial and temporal organization of the genome: current state and future aims of the 4D Nucleome Project, Mol Cell 83: 2624-2640 (2023), https://doi.org/10.1016/j.molcel.2023.06.018

Zhang, L., Chen, Y., Belmont, A.S., Measuring proximity of chromosome loci to defined nuclear compartments with TSA-seq, Chapter 8 in “Spatial Genome Organization”, Tom Sexton (Ed), Methods Molecular Biology, Vol. 2532: 145-186 (2022), Humana Press, New York, NY doi.org/10.1007/978-1-0716-2497-5_8

Belmont, A.S., Nuclear Compartments: An incomplete primer to nuclear compartments, bodies, and genome organization relative to nuclear architecture, Cold Spring Harbor Perspectives in Biology (2021), a041268 (doi: 10.1101/cshperspect.a041268)

Zhang, L., Zhang, Y., Chen, Y., Gholamalamdari, O., Wang, Y., Ma, J., Belmont, A.S, TSA-seq reveals a largely conserved genome organization relative to nuclear speckles with small position changes tightly correlated with gene expression changes, Genome Research (2021), 31: 251-264, doi:10.1101/gr.266239.120, PMID: 33355299

Dopie, J., Sweredoski, M.J., Moradian, A., Belmont, A.S., Tyramide Signal Amplification Mass Spectrometry (TSA-MS-ratio) Identifies Nuclear Speckle Proteins, JCB, (2020), 219: e201910207. doi: 10.1083/jcb.201910207

Zhao, B, Chaturvedi, P., Zimmerman, D.L., Belmont, A.S., Efficient and Reproducible Multigene Expression after Single-Step Transfection Using Improved BAC Transgenesis and Engineering Toolkit, ACS Synth Biol. (2020) doi: 10.1021/acssynbio.9b00457

Kim, J., Khanna, N., A.S. Belmont, Gene expression amplification by nuclear speckles, JCB (2020) 219 (1): e201904046, doi: 10.1083/jcb.201904046

Kim, J., Khanna, N., Han, K.Y., Ha, T., A. S. Belmont, Nuclear speckle fusion via long-range directional motion regulates the number and size of speckles in live cells, JCS (2019) 132(8). pii: jcs226563. doi: 10.1242/jcs.226563, PMID:30858197

Chen, Y., Zhang, Y., Wang, Y., Zhang, L., Brinkman, E.K., Adam, S.A., Goldman, R., van Steensel, B., Ma, J., Belmont, A.S., Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler, JCB 217:4025-4048 (2018), PMID:30154186

Tasan, I, Sustackova, G., Zhang, L, Kim, J., Sivaguru, M., HamediRad M.M, Wang, Y., Justin Genova, J., Ma, J., Belmont, A.S., and H. Zhao, CRISPR/Cas9-mediated Knock-in of an Optimized TetO Repeat for Live Cell Imaging of Endogenous Loci, Nucleic Acids Research, 46(17):e100 (2018) doi: 10.1093/nar/gky501, PMID:29912475, PMC6158506

Chaturvedi, P., Zhao, B, Zimmerman, D.L., and A.S. Belmont, Stable and Reproducible Transgene Expression Independent of Proliferative or Differentiated State Using BAC TG-EMBED, Gen Ther. 2018, 25(5):376-391. doi: 10.1038/s41434-018-0021-z, PMID:29930343, PMC6195848

van Steensel, B., Belmont, A.S., Lamina-Associated Domains: Links with Chromosome Architecture, Heterochromatin, and Gene Repression, Cell 169: 780-791 (2017), PMC5532494, PMID:28525751

Deng, X, Zhironkina, O.A., Cherepanynets, V.D., Strelkova, O.S., Kireev, I.I., Belmont, A.S., Cytology of DNA Replication Reveals Dynamic Plasticity of Large-scale Chromatin Fibers, Current Biology 26:2527-34 (2016), PMC5039087, PMID: 27568589

Recent Publications

Dekker, J., Alber, F., Aufmkolk, S., Beliveau, B. J., Bruneau, B. G., Belmont, A. S., Bintu, L., Boettiger, A., Calandrelli, R., Disteche, C. M., Gilbert, D. M., Gregor, T., Hansen, A. S., Huang, B., Huangfu, D., Kalhor, R., Leslie, C. S., Li, W., Li, Y., ... Zhong, S. (2023). Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project. Molecular cell, 83(15), 2624-2640. https://doi.org/10.1016/j.molcel.2023.06.018

Xiong, X., Tasan, I., Yang, C., Zhang, M., Hernandez Gonzalez, G. A., Liu, S., Chaturvedi, P., Belmont, A. S., & Zhao, H. (2023). Imaging Method Using CRISPR/dCas9 and Engineered gRNA Scaffolds Can Perturb Replication Timing at the HSPA1 Locus. ACS synthetic biology, 12(5), 1424-1436. https://doi.org/10.1021/acssynbio.2c00433

Belmont, A. S. (2022). Nuclear Compartments: An Incomplete Primer to Nuclear Compartments, Bodies, and Genome Organization Relative to Nuclear Architecture. Cold Spring Harbor Perspectives in Biology, 14(7), Article a041268. https://doi.org/10.1101/cshperspect.a041268

Zhang, L., Chen, Y., & Belmont, A. S. (2022). Measuring Cytological Proximity of Chromosomal Loci to Defined Nuclear Compartments with TSA-seq. In Methods in Molecular Biology (pp. 145-186). (Methods in Molecular Biology; Vol. 2532). Humana Press Inc.. https://doi.org/10.1007/978-1-0716-2497-5_8

Zhu, X., Zhang, Y., Wang, Y., Tian, D., Belmont, A. S., Swedlow, J. R., & Ma, J. (2022). Nucleome Browser: an integrative and multimodal data navigation platform for 4D Nucleome. Nature Methods, 19(8), 911-913. https://doi.org/10.1038/s41592-022-01559-3

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