Spatially resolved epigenomic profiling of single cells in complex tissues

Tian, Lu; Ang, Cheen Euong; Zhuang, Xiaowei

doi:10.1101/2022.02.17.480825

Cited by 6 publications

(5 citation statements)

References 77 publications

(122 reference statements)

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“…As a complementary technique, we have here presented a proof of concept that an activity profile can be inferred from structural data on a polymer. In future work, we propose to extend this method to chromatin tracing data ( 99 , 100 ), which measures the pairwise mean squared separation of genetic loci along with other attributes such as transcriptional ( 100 ) and epigenetic state ( 118 , 119 ).…”

Section: Discussionmentioning

confidence: 99%

Polymer folding through active processes recreates features of genome organization

Goychuk

Kannan

Chakraborty

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate. Moreover, chromatin motion varies with genomic coordinate, pointing toward a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers nonequilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward exploring whether active mechanisms contribute to shaping genome conformations, we discuss a data-driven approach.

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Section: Discussionmentioning

confidence: 99%

Polymer folding through active processes recreates features of genome organization

Goychuk

Kannan

Chakraborty

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…As a complementary technique, we have here presented a proof of concept that an activity profile can be inferred from structural data on a polymer. In future work, we propose to extend this method to DNA-MERFISH data (108), which measures the pairwise mean squared separation of genetic loci along with other attributes such as transcriptional (108) and epigenetic state (109, 110).…”

Section: Discussionmentioning

confidence: 99%

Polymer folding through active processes recreates features of genome organization

Goychuk

Kannan

Chakraborty

et al. 2022

Preprint

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From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate (ATP). Moreover, chromatin motion varies with genomic coordinate, pointing towards a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers non-equilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward disentangling active and passive mechanisms of folding, we discuss a data-driven approach to discern if and how active processes affect genome organization.

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“…Other spatial technologies need to be further improved to become accessible to the broad scientific community. However, first findings using spatial epigenomics 33 or metabolomics 34 in other organs were published recently and give hope that these technologies might become accessible to the broad scientific community soon. These technologies will certainly improve our understanding of spatial differences in heart after MI and also during heart failure development from other causes including heart failure with preserved ejection fraction.…”

Section: Spatial Omics In Cardiovascular Researchmentioning

confidence: 99%

Multiomic Spatial Mapping of Myocardial Infarction and Implications for Personalized Therapy

Schumacher

Kramann

2023

ATVB

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Ischemic heart disease including myocardial infarction is still the leading cause of death worldwide. Although the survival early after myocardial infarction has been significantly improved by the introduction of percutaneous coronary intervention, long-term morbidity and mortality remain high. The elevated long-term mortality is mainly driven by cardiac remodeling processes triggering ischemic heart failure and electric instability. Despite the new developments in pharmaco-therapy of heart failure, we still lack targeted therapies for cardiac remodeling and fibrosis. Single-cell and genomic technologies allow us to map the human heart at unprecedented resolution and allow to gain insights into cellular and molecular heterogeneity. However, these technologies rely on digested tissue and isolated cells or nuclei and thus lack spatial information. Spatial information is critical to understand tissue homeostasis and disease and can be utilized to identify disease-driving cell populations and mechanisms including cellular cross-talk. Here, we discuss recent advances in single-cell and spatial genomic technologies that give insights into cellular and molecular mechanisms of cardiac remodeling after injury and can be utilized to identify novel therapeutic targets and pave the way toward new therapies in heart failure.

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Spatially resolved epigenomic profiling of single cells in complex tissues

Cited by 6 publications

References 77 publications

Polymer folding through active processes recreates features of genome organization

Polymer folding through active processes recreates features of genome organization

Polymer folding through active processes recreates features of genome organization

Multiomic Spatial Mapping of Myocardial Infarction and Implications for Personalized Therapy

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