About
Andrew S. Belmont is a professor of Cell & Developmental Biology, Biophysics, and Quantitative Biology at the University of Illinois. His research focuses on chromatin structure, gene regulation, and nuclear architecture. Belmont's laboratory investigates how 10 and 30 nm chromatin fibers fold into interphase and mitotic chromosomes, how interphase chromosomes are moved and positioned within nuclei, and the implications of these processes for DNA functions such as transcription and replication. His team employs molecular biology, cell biology, genetics, and microscopy techniques to visualize nuclear positioning and folding dynamics of specific chromosome regions and gene loci, relating these to gene expression regulation. Belmont has developed methods for tagging specific gene loci in live cells using operator repeats and CRISPR-based approaches, enabling detailed studies of gene loci behavior. His work has revealed that different large-scale chromatin compaction states are tightly correlated with nuclear positioning and that directed, long-range chromosome movements are coupled to transcriptional activation. Recently, his research has focused on the relationship between gene expression and nuclear genome positioning relative to nuclear speckles and other nuclear condensates, utilizing innovative genomic and microscopy methods such as TSA-seq to map genome-wide nuclear distances. Belmont's contributions have advanced understanding of nuclear organization and its influence on gene regulation, and he has received recognition through NIH grants and publications in prominent scientific journals.
Research topics
- Genetics
- Biology
- Computational biology
- Physics
- Cell biology
Selected publications
Molecular Cell · 2026-03-01 · 2 citations
articleOpen access2025-02-24
peer-reviewOpen accessSenior authorModels of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-25 · 2 citations
preprintOpen accessSenior authorCorrespondingA subset of highly active chromosomal "hot zones" reproducibly positions adjacent to nuclear speckles (NS). Genes within these regions amplify their expression only with NS contact. However, gene expression differences inversely correlate with differences in NS distance, genome-wide. We hypothesized the existence of additional gene expression "niches" away from, but spatially correlated with, NS. Here we report the identification of two dynamic perispeckle patterns of protein concentrations extending outwards from NS and persisting even after NS are eliminated. Highly active chromosome regions which weakly associate with NS instead show close, NS-independent association with these perispeckle patterns. Additionally, transcripts from model intron-containing versus intronless genes associate differentially with these two patterns. While genes within NS-associated genomic regions are predominantly downregulated upon NS depletion, genes associated with perispeckle patterns are biased towards upregulation. We suggest the interchromatin space is partitioned into additional gene expression "niches"- surrounding and extending from NS - that may be involved in mRNA and gene dynamics.
An integrated view of the structure and function of the human 4D nucleome
Nature · 2025-12-17 · 19 citations
articleOpen accessto map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.
Nonrandom interchromatin trafficking through dynamic multiphase speckle connections
bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-23 · 2 citations
preprintOpen accessSenior authorCorrespondingNuclear speckles (NS) enhance the expression of NS-associated genes, possibly by elevating local levels of factors involved in multiple steps of gene expression. While dozens of large NS are distributed throughout interchromatin regions, the extent to which NS components dynamically redistribute between NS to adjust to local physiological demands remains unknown. Here we used live-cell imaging of endogenous NS proteins to identify an interchromatin network of connections that functionally link NS throughout the nucleus. Over timescales ranging from tens of seconds to minutes, NS material undergoes bulk transfer through these connections. Multiphase NS-connecting structures form through the dynamic juxtapositions of multiple NS component phases. Each phase exhibits distinct yet recurrent viscoelastic dynamics, but together, they integrate into a more stable, multiphase, NS-connecting structure in an ATP-and transcription-dependent manner. Our findings reveal the existence of a cellular mechanism that facilitates coordinated inter-NS protein trafficking through multiphase connections.
eLife · 2025-03-25 · 1 citations
preprintOpen accessSenior authorAbstract Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
2025-04-25
peer-reviewOpen accessSenior authorNew insights into nuclear genome organization were generated by comparing genome localization relative to three major nuclear locales- nuclear lamina, nuclear speckles, and nucleoli- across several human cell lines.
2025-03-25
peer-reviewOpen accessSenior authorModels of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
eLife · 2025-02-24 · 1 citations
preprintOpen accessSenior authorAbstract Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-03 · 1 citations
preprintOpen accessSenior authorCorrespondingA small fraction of the genome positions reproducibly near nuclear speckles (NS), increasing expression and/or splicing efficiency of NS-associated genes. How specific genomic regions target to NS remains unclear. Here, we demonstrate that establishment of genome-wide NS-association occurs independent of active transcription. We show that DNA sequences derived from NS-associated regions integrated as transgenes autonomously target to NS. By systematically dissecting one such genomic locus, the COL1A1-SGCA locus, we identified redundant NS-targeting cis regulatory elements, including a ∼600 bp fragment with 17 binding motifs for 8 transcription factors (TFs). Four NS-targeting TFs within this fragment contain acidic activation domains (AADs) that provide both chromatin-context and transcription-dependent NS-targeting, a property that appears common among several other tested AADs. A subset of acidic activator TFs contain an additional, transcription-independent NS-targeting activity. Our findings establish diverse and partially redundant NS-targeting activities, which may facilitate dynamic gene positioning at NS periphery for context-specific transcriptional responses.
Recent grants
NIH · $1.1M · 2017
NIH · $10.4M · 2020–2026
Biological Validation Development
NIH · $16.6M · 2022
NIH · $565k · 1995
NIH · $27k
Frequent coauthors
- 72 shared
Bas van Steensel
The Netherlands Cancer Institute
- 71 shared
Liguo Zhang
University of Illinois Urbana-Champaign
- 69 shared
Jian Ma
- 66 shared
Yang Zhang
San Diego Biomedical Research Institute
- 64 shared
Yuchuan Wang
San Diego Biomedical Research Institute
- 64 shared
Tom van Schaik
Oncode Institute
- 61 shared
David M. Gilbert
San Diego Biomedical Research Institute
- 58 shared
Omid Gholamalamdari
University of Illinois Urbana-Champaign
Labs
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