Дальние Поликомб-опосредованные контакты хроматина в клетках головного мозга человека / Long-range Polycomb-mediated chromatin interactions in human brain cells тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Плетенев Илья Андреевич

• Плетенев Илья Андреевич
• кандидат наук
• 2026

Оглавление диссертации кандидат наук Плетенев Илья Андреевич

Table of Contents

Introduction

Chapter 1. Literature review

1.1 Overview of the human cerebral cortex

1.1.1 Cell types of the human cerebral cortex

1.1.2 Development and maturation of the human cerebral cortex

1.2 Chromatin in human cells

1.2.1 DNA methylation

1.2.2 Nucleosomes

1.2.3 Three-dimensional chromatin structure

1.3 Polycomb-group proteins

1.3.1 Composition of PRC1 and PRC2

1.3.2 Polycomb domain formation and spreading

1.3.3 Regulation of transcription

1.3.4 Polycomb condensates

1.3.5 Polycomb in cortical development

1.4 3C-based methods for studying 3D genome architecture

Chapter 2. Materials and methods

2.1 ChIP-seq data generation

2.2 ChIP-seq data processing

2.3 RNA-seq data processing

2.4 Hi-C data processing

2.5 Hi-C iterative correction

2.6 Analysis of Hi-C compartments

2.7 Snm3C-seq data processing

2.8 Annotation of neuronal dot anchors

2.9 Automatic annotation of neuronal dots

2.9.1 Selection of candidate regions

2.9.2 Feature selection

2.9.3 Logistic regression model

2.9.4 Combined manual and automatic annotations

2.10 Analysis of neuronal dots

2.10.1 Hi-C

2.10.2 snm3C-seq

2.11 Joint analysis of neuronal dots and gene expression in the adult brain dataset

2.12 Analysis of snRNA-seq data for the developing brain

2.13 DNA methylation data processing

Chapter 3. Three-dimensional chromatin organization of cells in the brain

cortex

3.1 Analysis of Hi-C compartments

3.2 NeuN(+) chromatin is shaped around networks of long-range contacts between H3K27me3 loci

3.3 Genes from human neuronal dots are coupled with PcG proteins in

mouse

3.4 Five genomic regions form neuronal dots exclusively in excitatory neurons

Chapter 4. Ultra long-range Polycomb-coupled interactions facilitate

neuronal subtype identity

4.1 Excitatory vs inhibitory neurons in the cortex

4.2 All neuronal and glial subtypes

4.3 Polycomb-repressed loci have low chromatin compaction

4.4 Neuronal dots emerge during brain development

4.5 Neuronal dots are characterized by the binding of the PRC1 complex

4.6 Interplay of neuronal dots and DNA methylation

Conclusions

Acknowledgments

List of Abbreviations

Glossary

Bibliography

Appendix A. Supplementary figures and tables

Введение диссертации (часть автореферата) на тему «Дальние Поликомб-опосредованные контакты хроматина в клетках головного мозга человека / Long-range Polycomb-mediated chromatin interactions in human brain cells»

Introduction

Research topic relevance. The development of a multicellular organism requires that genetically identical cells adopt distinct identities and functions. This process is governed by precise control of gene expression, achieved through epigenetic mechanisms including DNA methylation, nucleosome repositioning, histone post-translational modifications, and higher-order chromatin folding [1]. These processes direct RNA polymerase II activity and ensure the correct execution of developmental programs [1].

In recent years, increasing attention has been directed toward the role of the spatial organization of chromatin, also referred to as the 3D genome, in regulating gene expression [2]. Alterations in 3D chromatin conformation can bring a promoter into contact with genomic regions that either enhance or repress its transcription, or conversely, isolate it from such regulatory elements [2]. Throughout development, the 3D genome undergoes dynamic reorganization to ensure the proper execution of gene expression programs [3]. Conversely, disruption of chromatin architecture can impair these regulatory interactions, leading to aberrant gene expression and developmental abnormalities [4], thereby underscoring the fundamental importance of chromatin organization for organism development.

The key players that regulate gene expression during organism development are Polycomb-group (PcG) proteins, a set of transcription factors, histone modifying enzymes, and their co-factors that form two Polycomb Repressive Complexes (PRCs): PRC1 and PRC2 — with the main function of transcriptional repression [5; 6]. In mammals, Polycomb proteins are essential for key stages of embryonic development, including embryonic stem cell differentiation [7], gastrulation [8], neurulation [9], and organogenesis [10]. This profound role stems from the ability of Polycomb complexes to target a wide range of genes encoding developmental transcription factors and cell type markers [11]. In addition, Polycomb complexes can act as oncogenes or tumor suppressor genes, highlighting their significance in biomedical research [12].

An important feature of Polycomb complexes is their ability to modify 3D chromatin organization by creating long-range interactions: loops and chromatin condensates [5]. These structures facilitate Polycomb spreading along the genome [13; 14] and long-term maintenance of the repressive state [15; 16]. Polycomb-coupled long-

range interactions are functionally important for normal axial development [17] and spermatogenesis in mice [15].

In developmental biology, particular attention has been given to the role of Poly-comb proteins in nervous system development, especially in cortical formation [18]. It was demonstrated that Polycomb complexes are essential for endoderm fate specification [19], dorsal-ventral patterning of the telencephalon [20], neurogenesis [9; 21; 22], and neuronal subtype specification [23]. In contrast, their role in organizing the neural 3D genome is less understood. During embryonic stem cell differentiation into cortical neurons, Polycomb-mediated loops have been shown to link promoters of repressed genes and to disappear upon gene activation [24].

The advent of genome-wide chromatin conformation capture methods, such as Hi-C and snm3C-seq, has enabled high-resolution studies of the 3D genome in diverse tissues, including the brain [25; 26]. Whole-genome 3D chromatin structure changes markedly during cortical development [27; 28] and differs across neural cell types [29—31]. To date, however, most studies of 3D chromatin conformation in the nervous system have been conducted in mice [24; 28; 32—40], human cell cultures [41—48], or brain organoids [49]. Data from human post-mortem brain samples have only recently become available. [27; 29—31; 50—52], and even fewer datasets separate neurons from other brain cell types using fluorescence-activated nuclear sorting or single-cell approaches. [27; 29—31; 50]. These studies explore major chromatin features — including chromatin compartments, loops, and topologically associating domains — yet the contribution of Polycomb complexes to 3D genome architecture remains largely unexplored.

The goal of this research is to investigate the role of Polycomb-group protein interactions in the three-dimensional chromatin structure of the human brain.

To achieve the goal of the dissertation, the following problems are addressed:

1. Analyze bulk Hi-C data from human cortical neurons and NeuN(-) brain cells, as well as single-nucleus methyl-3C sequencing (snm3C-seq) data from both adult and developing human cortex.

2. Assess genome segregation into active and inactive compartments in neurons relative to other brain cells.

3. Determine the genomic positioning of Polycomb-group protein interactions.

4. Characterize the properties of the loci involved in Polycomb-group protein interactions.

5. Identify genes potentially regulated by Polycomb-group protein interactions.

6. Examine the relationship between Polycomb-group protein interactions and the binding of Polycomb-group proteins using ChIP-seq data.

7. Using snm3C-seq data, evaluate whether Polycomb-group protein interactions show cell-type specificity across different subtypes of neurons.

8. Investigate the emergence and dynamics of Polycomb-group protein interactions during brain development.

Scientific novelty:

1. For the first time, Hi-C data from the Wernicke's area of the human cerebral cortex has been analyzed.

2. For the first time, long-range Polycomb-group protein interactions have been comprehensively characterized in human neurons.

3. For the first time, the association between long-range Polycomb-group protein interactions and the transcription of neuronal transcription factors has been demonstrated across neuronal subtypes.

4. For the first time, the hypothesis that strong long-range Polycomb-group protein interactions are a unique feature of mature human neurons has been proposed.

Theoretical and practical significance. It is known that proper three-dimensional chromatin organization is essential for neural development. Studying chromatin architecture in the developing and mature brain may reveal mechanisms underlying developmental abnormalities. Disruption of 3D chromatin organization has also been linked to cancer, thus, studying the neuronal 3D genome could help elucidate the origins of cancers such as neuroblastoma and glioblastoma. Moreover, Polycomb dysregulation at oncogenes or tumor suppressor genes is known to promote cancer progression, underscoring the importance of Polycomb research.

Main results submitted for the defence:

1. Genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells.

2. Neuronal chromatin is characterized by a network of long-range Polycomb-mediated contacts in neurons that is nearly absent in other brain cells.

3. Interacting loci brought together by Polycomb contain developmental transcription factor genes including ones responsible for neuronal differentiation into subtypes.

4. Long-range Polycomb-mediated contacts in neurons originate after birth and have specificity for neuronal subtypes.

5. Cumulative contact frequency is positively correlated with active transcription and associated with compartment organization.

Validity of the obtained results is supported by the following factors: all analyzed data meet standard quality control criteria; the results are validated by statistical analysis; and they are consistent with findings from other researchers.

Personal contribution of the author. For the study on cumulative contact frequency [201] described in Chapter 2, the author conducted bioinformatics analysis and prepared figures in collaboration with Margarita Samborskaia and Aleksandra Galit-syna.

For the study on neuronal 3D genome [202] described in Chapter 3, the author conducted bioinformatics analysis and prepared figures mentioned in the chapter, except Figure 3.1A, which was prepared by Ekaterina Khrameeva (E.E.K).

For the study on Polycomb-mediated long-range interactions in neuronal subtypes described in Chapter 4, bioinformatics analysis and figure preparation were carried out in collaboration with Nikita Vaulin (N.V.), Ekaterina Kuznechenkova (E.K.), and Anastasia Soldatenkova (A.S.).

- In Sections 4.1 and 4.2, the algorithm for automatic annotation of neuronal dot anchors was designed by the author and implemented by A.S. under supervision of the author. The analysis of Polycomb-mediated dots in subtypes of adult neurons was conducted by N.V. and the author.

- In Sections 4.3 and 4.5, bioinformatics analysis was done by E.K. under supervision of the author. The author also contributed to figure preparation.

- In Sections 4.4 and 4.6, both the bioinformatics analysis and figure preparation were performed by the author.

Approbation. The main results of this thesis have been described in two scientific publications [201; 202] in journals indexed in the Web of Science and Scopus databases and presented at the following conferences:

1. Information Technologies and Systems, 2022, Ognikovo, Russia.

2. Moscow Conference on Computational Molecular Biology, 2023, Moscow, Russia.

3. Chromosome, 2023, Novosibirsk, Russia.

4. Bioinformatics of Genome Regulation and Structure/Systems Biology, 2024, Novosibirsk, Russia.

Dissertation structure. The dissertation consists of introduction, 4 chapters, conclusion, and 1 appendix. The dissertation is 134 pages long, including 57 figures and 8 tables. Bibliography contains 202 titles.

Заключение диссертации по теме «Другие cпециальности», Плетенев Илья Андреевич

Conclusions

Polycomb complexes are essential for correct neural development, though their impact on the 3D genome remains poorly understood. This thesis investigated the role of Polycomb-group protein interactions in the three-dimensional chromatin structure of the human brain. The main results of the dissertation are:

1. It was determined that genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells.

2. It was shown that neuronal chromatin in the brain cortex is characterized by a network of long-range Polycomb-mediated contacts that is nearly absent in other brain cells.

3. It was demonstrated that interacting loci brought together by Polycomb contain developmental transcription factor genes including ones responsible for neuronal differentiation into subtypes. The expression of these genes in different neuronal subtypes anticorrelate with the presence of Polycomb-mediated contact.

4. It was shown that cumulative contact frequency is positively correlated with active transcription and associated with compartment organization.

Studying the 3D genome of the human brain is challenging because current experimental methods are highly invasive. This study therefore uses human postmortem brain tissue as a model. Although widely regarded as suitable, the quality of postmortem samples depends heavily on the postmortem interval, which is typically long for human samples. Another limitation is that postmortem tissue provides only a static snapshot of brain state and cannot be used for perturbation experiments. A promising alternative is primary mouse neuron cultures, which recapitulate key neuronal features while allowing diverse experimental manipulations. This approach opens several new research directions.

To assess how Polycomb abundance influences Polycomb-mediated interactions and gene expression, conditional overexpression or knockout of specific Polycomb subunits could be employed. Particular interest lies in subunits with protein domains involved in dimerization and chromatin condensate formation, such as the CaPS domain of CBX2 and the SAM domain of PHC.

Several transcription factors repressed by PcG contacts — such as FEZF2, SATB2, DLX1/2, and SOX2 — are key regulators of neuronal differentiation and could,

in theory, recruit or displace Polycomb complexes, thereby establishing or disrupting Polycomb-mediated interactions. Conditional knockout or overexpression of these transcription factor genes could help clarify this potential interplay.

Another research direction in postmortem human brain tissue is to examine the composition and genomic positioning of Polycomb proteins in both the developing and adult brain. ChIP-seq or analogous data are currently lacking but could yield important insights into the role of Polycomb composition in neuronal long-range contact formation.

Interacting loci occupied by Polycomb proteins are sometimes considered a distinct chromatin subcompartment. In neurons, this Polycomb subcompartment could, in principle, influence the strength of other compartments, potentially explaining differences in compartmentalization between neuronal and non-neuronal cells. Physical modeling of subcompartments may help address this question.

Another open question concerns the presence of long-range, high-intensity Poly-comb interactions in other brain regions and non-brain tissues. Moreover, data from the first trimester of development are particularly valuable, as many PcG contacts are likely established during this period.

Taken together, this work describes previously unexplored long-range Polycomb-mediated chromatin interactions in developing and mature human neurons and provides evidence for their importance in neuronal subtype specification. These findings extend our understanding of Polycomb function in the human brain and provide a foundation for future studies on how 3D genome architecture contributes to neuronal identity and diversity.

Список литературы диссертационного исследования кандидат наук Плетенев Илья Андреевич, 2026 год

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Publications of the Author on the Subject of the Dissertation

201. Samborskaia M. D., Galitsyna A., Pletenev I., Trofimova A., Mironov A. A., Gelfand M. S., Khrameeva E. E. Cumulative Contact Frequency of a Chromatin Region Is an Intrinsic Property Linked to Its Function // PeerJ. — 2020. — Aug. — Vol. 8. - URL: https://doi.org/10.7717/peerj.9566 (visited on 01/14/2021).

202. Pletenev I. A., Bazarevich M., Zagirova D. R., Kononkova A. D., Cherkasov A. V., Efimova O. I., Tiukacheva E. A., Morozov K. V., Ulianov K. A., Komkov D., Tvorogova A. V., Golimbet V E., Kondratyev N. V., Razin S. V., Khaitovich P,

Ulianov S. V., Khrameeva E. E. Extensive Long-Range Polycomb Interactions and Weak Compartmentalization Are Hallmarks of Human Neuronal 3D Genome // Nucleic Acids Research. — 2024. — June. — Vol. 52, no. 11. — P. 6234-6252.

113 Appendix А Supplementary figures and tables