Myc-induced anchorage of the rDNA IGS region to nucleolar matrix modulates growth-stimulated changes in higher-order rDNA architecture

Abstract

Chromatin domain organization and the compartmentalized distribution of chromosomal regions are essential for packaging of deoxyribonucleic acid (DNA) in the eukaryotic nucleus as well as regulated gene expression. Nucleoli are the most prominent morphological structures of cell nuclei and nucleolar organization is coupled to cell growth. It has been shown that nuclear scaffold/matrix attachment regions often define the base of looped chromosomal domains in vivo and that they are thereby critical for correct chromosome architecture and gene expression. Here, we show regulated organization of mammalian ribosomal ribonucleic acid genes into distinct chromatin loops by tethering to nucleolar matrix via the non-transcribed inter-genic spacer region of the ribosomal DNA (rDNA). The rDNA gene loop structures are induced specifically upon growth stimulation and are dependent on the activity of the c-Myc protein. Matrix-attached rDNA genes are hypomethylated at the promoter and are thus available for transcriptional activation. rDNA genes silenced by methylation are not recruited to the matrix. c-Myc, which has been shown to induce rDNA transcription directly, is physically associated with rDNA gene looping structures and the intergenic spacer sequence in growing cells. Such a role of Myc proteins in gene activation has not been reported previously.

Nuclear PI3K signaling in cell growth and tumorigenesis

“…Among other roles, nuclear c-Myc controls the transcription of UBF, directly binds rDNA in the nucleolus, mediates assembly of SL1 on rDNA promoters, facilitates UBF and TATA-binding protein (TBP) assembly into the PIC, and increases histone acetylation and chromatin accessibility (Poortinga et al, 2004 ; Grandori et al, 2005 ). The interaction of c-Myc with rDNA, found to occur at intergenic spacer regions (IGSs), is important for epigenetically non-silenced and promoter-hypomethylated rDNA attachment to the nuclear matrix for transcriptional activation (Littlewood et al, 1995 ; Shiue et al, 2014 ). Matrix attachment of rDNA occurs in response to growth factor stimulation, a signal that may be relayed to c-Myc through the PI3K pathway.…”

The loss of ATRX/DAXX complex disturbs rDNA heterochromatinization and promotes development of glioma

“…For example, promoter and coding (P&C) regions are characterized by a high GC content and are often responsible for the transcriptional activity of rDNA (2). Meanwhile, IGS regions tend to have normal GC content and are involved in mediating nucleolar matrix-attachments (3). Due to the presence of multiple copies of tandem repeat genes, there are two strategies which have been proposed for the regulation of rDNA transcription in cells: 1) growth factors, nutrients, or a range of stress factors regulate the transcriptional efficiency of RNA polymerase I (4), or 2) epigenetic modifications regulate the ratio of active rDNA to silent rDNA and transcriptional potency (5).…”

Reproduction of the FC/DFC units in nucleoli

“…Data of electron microscopy and electron tomography suggest that active rRNA genes form coils surrounding FC. 31 More recent studies using 3C assays, 32,[37][38][39][40][41][42][43][44][45][46] reviewed in ref., 47 show that the active genes, supposedly localized in the FC/DFC units, form loops. In each of these loops, promoter is joined to terminator through a number of proteins, among which transcription termination factor 1 (TTF-1) and protooncogene c-Myc seem to be particularly important; 48 both are bound to non-transcribed spacer regions and regulate association of epigenetically activated rDNA genes to the nucleolar matrix.…”

“…In each of these loops, promoter is joined to terminator through a number of proteins, among which transcription termination factor 1 (TTF-1) and protooncogene c-Myc seem to be particularly important; 48 both are bound to non-transcribed spacer regions and regulate association of epigenetically activated rDNA genes to the nucleolar matrix. 39 According to a core-helix model proposed by Denissov et al, 32 the transcribing pol I complexes driven by actin revolve around the SL1 (selectivity factor 1) containing core, which is situated in FC and serves as an anchor for both promoter and terminator of the rDNA repeat; the nascent rRNAs exit radially into DFC.…”