The <scp>RNA</scp> helicase <scp>DHX</scp>9 establishes nucleolar heterochromatin, and this activity is required for embryonic stem cell differentiation

Leone, Sergio; Bär, Dominik; Slabber, C.; Dalcher, Damian; Santoro, Raffaella

doi:10.15252/embr.201744330

Cited by 44 publications

(67 citation statements)

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“…The responsible factor for the establishment of silent rRNA genes is the nucleolar remodeling complex (NoRC), which comprises TTF-1 interacting protein 5 (TIP5) and SNF2H, a member of the ISWI subfamily and catalytic subunit of several chromatin-remodeling complexes [20][21][22] ( Figure 1B). NoRC is recruited to rRNA genes through its association with the long noncoding (lnc) RNA pRNA; pRNA mediates the interaction with TTF-1, which binds the terminator DNA element T 0 located in the rRNA gene promoter [23][24][25]. pRNA is generated by the RNA helicase DHX9-mediated processing of the intergenic spacer (IGS)-rRNA, a transcript that originates from the rRNA spacer promoter and which is located 2 kb upstream of the main gene promoter in mouse cells [24,26] (Figure 1A).…”

Section: Trends In Geneɵcsmentioning

confidence: 99%

Nucleolus and rRNA Gene Chromatin in Early Embryo Development

Kresoja‐Rakic

Santoro

2019

Trends in Genetics

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The nucleolus is the largest substructure in the nucleus and forms around the nucleolar organizer regions (NORs), which comprise hundreds of rRNA genes. Recent evidence highlights further functions of the nucleolus that go beyond ribosome biogenesis. Data indicate that the nucleolus acts as a compartment for the location and regulation of repressive genomic domains and, together with the nuclear lamina, represents the hub for the organization of the inactive heterochromatin. In this review, we discuss recent findings that have revealed how nucleolar structure and rRNA gene chromatin states are regulated during early mammalian development and their contribution to the higher-order spatial organization of the genome. The Multifunctional Nucleolus: From Ribosome Producer to Organizer of Genome Architecture The nucleolus (see Glossary) is the largest subnuclear compartment of the cell and forms around regions of chromosomes containing stretches of tandem repetitive rRNA genes, known as nucleolar organizer regions (NORs). The nucleolus is responsible for the production of ribosomes, a highly regulated process that is essential for growth and development. Ribosome biogenesis is initiated in the nucleolus by RNA polymerase I (Pol I), which, together with a dedicated set of basal transcription factors, such as TIF1A, the TBP-TAFI complex SL1, and the DNA architectural upstream binding factor (UBF) [1,2], transcribes hundreds of rRNA genes to generate 45S/47S pre-rRNA in mammalian cells (Figure 1A). This rRNA precursor is chemically modified and processed to form 28S, 18S, and 5.8S rRNAs, which are then assembled with ribosomal proteins and 5S rRNA and exported from the nucleus to give rise to active ribosomes in the cytoplasm [3]. Increasing evidence suggests that the function of the nucleolus and rRNA genes goes beyond ribosome biogenesis. One aspect that has received significant interest over the past decade is the link between the nucleolus and rRNA genes with the organization of genome architecture. Clustering of heterochromatin at nucleoli is a phenomenon that occurs in all cells. Furthermore, regions located close to the nucleolus (nucleolar-associated domains, NADs) have low gene densities, low transcriptional levels, and repressive histone modifications [4-8]. Since similar heterochromatic and repressive regions are also located to the nuclear lamina, the nucleolus, together with the nuclear lamina, can be considered the hub for the organization of the inactive chromatin in the cell [8-10]. In this review, we address the role of the nucleolus as a subnuclear compartment for the organization of heterochromatin. We discuss recent findings that have revealed how nucleolar structure and rRNA gene chromatin states are regulated during gametogenesis and early mammalian development, and their contribution in the higher-order spatial organization of the genome. Nucleolus and rRNA Genes in Somatic Cells In somatic cells, the nucleolus is a membraneless compartment with a peculiar tripartite architecture: the fibrillar cen...

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Section: Trends In Geneɵcsmentioning

confidence: 99%

Nucleolus and rRNA Gene Chromatin in Early Embryo Development

Kresoja‐Rakic

Santoro

2019

Trends in Genetics

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“…8B ), suggesting that the function of TIP5 in ESCs can be directed via the remodeling complex NoRC complex. Moreover, we detected all known and previously validated TIP5-interactors in differentiated cells such as DNMT1, PARP1 and DHX9 20, 21, 25, 26 . Remarkably, among the top TIP5-interacting proteins we found Topoisomerase 2A (TOP2A) and structural maintenance of chromosomes protein 3 (SMC3), which is part of the cohesin complex ( Fig.…”

Section: Resultsmentioning

confidence: 78%

“…In differentiated cells, TIP5 is mainly localized in nucleoli, associates with ribosomal RNA (rRNA) genes and establishes their epigenetic silencing 20, 22, 23 . In contrast, in ESCs, recruitment of TIP5 to rRNA genes and its ability to silence rRNA genes is impaired through a long non-coding RNA-mediated mechanism 24, 25 .…”

Section: Resultsmentioning

confidence: 99%

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TIP5 safeguards genome architecture of ground-state pluripotent stem cells

Dalcher

Tan

Bersaglieri

et al. 2019

Preprint

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1Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance 2 contacts between loci of similar chromatin states. However, how genome compartmentalization is 3 regulated remains elusive. We analyzed two closely and developmentally related pluripotent cell 4 types: ground-state ESCs that have an open and active chromatin and developmentally advanced 5 ESCs that display a more closed and repressed state. We show that these two ESC types differ in 6 their regulation of genome organization due to their differential dependency on TIP5, a component of 7 the chromatin remodeling complex NoRC. We show that TIP5 interacts on ESC chromatin with 8 SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. TIP5 associates with sub-domains within the 9 active A compartment that strongly intersect through long-range contacts in ESCs. We found that only 10 ground-state chromatin requires TIP5 to limit the invasion of active domains into repressive 11 compartments. Depletion of TIP5 increased chromatin accessibility particularly at B compartments and 12 decreased their repressive features. Furthermore, TIP5 acts as a barrier for the repressive H3K27me3 13 spreading, a process that also requires TOP2A activity. Finally, ground-state ESCs require TIP5 for 14 growth, differentiation capacity, and correct expression of developmental genes. Our results revealed 15 the propensity of open and active chromatin domains to invade repressive domains, an action 16 counteracted by chromatin remodeling and the relief of chromatin torsional stress. This effort in 17 controlling open/active chromatin domains is required to establish active and repressed genome 18 partitioning and preserves cell function and identity. 19 20 21 22 Introduction 1 The 3D genome organization is functionally important for correct execution of gene expression 2 programs. Chromosomes have an intrinsic tendency to segregate into compartments based on the 3 local epigenetic landscape and transcriptional activity. At the megabase scale, the genome can be 4 divided into two compartments, called A and B compartments, which are estimated by an eigenvector 5 analysis of the genome contact matrix after normalization by the observed-expected method 1 . 6 Genomic contacts predominately occur between loci belonging to the same compartment. 7 Compartment A is highly enriched for open and active chromatin whereas compartment B is enriched 8 for closed and repressed chromatin. Furthermore, long-distance contacts have been shown to occur 9 between domains with similar chromatin states 2 . Removal or depletion of chromatin-associated 10 cohesin eliminates all loop domains and increased compartmentalization 3-6 . The opposite effect was 11 achieved by increasing the residence time of cohesins on DNA, which leads to extension of chromatin 12 loops and a less strict segregation between A and B compartments with a decrease of far-cis contacts 13 5 . In contrast to topologically associating domains (TAD) boundaries, which are generally conserved 14 among cell types, ...

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“…DHX 9, also known as RNA helicase A or Nuclear DNA Helicase II, is a DNA/RNA helicase from the DEAH-box helicase family involved in regulation of transcription [135À137] and translation [138,139], DNA replication [140], embryonic stem cell differentiation [141], as well as genome repair and maintenance [142À144]. In addition, DHX9 is also present in several immune pathways.…”

Section: Dhx9mentioning

confidence: 99%