Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus

Kumar, Pranaw; Bischof, Oliver; Purbey, Prabhat Kumar; Notani, Dimple; Urlaub, Henning; Dejean, Anne; Galande, Sanjeev

doi:10.1038/ncb1516

Cited by 208 publications

(86 citation statements)

References 44 publications

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“…Next, we used a matrix association assay (30) to experimentally identify regions of the rDNA repeat that are matrix attached. Figure 2A summarizes the procedures used to study the association of rDNA sequences with the nucleolar matrix.…”

Section: Resultsmentioning

confidence: 99%

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

Shiue

Nematollahi-Mahani

Wright

2014

Nucleic Acids Research

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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.

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Section: Resultsmentioning

confidence: 99%

“…Analogous to the 3C assay, the MAR-loop assay has been used to detect DNA sequences that are held in close proximity to each other as a result of interaction with the nuclear matrix (30). Unlike the 3C assay, it is not necessary to use formaldehyde cross-linking to maintain integrity of the samples in the MAR-loop assay.…”

Section: Resultsmentioning

confidence: 99%

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

Shiue

Nematollahi-Mahani

Wright

2014

Nucleic Acids Research

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“…Recently, SATB1 has attracted considerable attention due to its capability to coordinate regulation for many genes which are significantly associated with the growth, invasion and metastasis of a variety of malignancies [14], [15], indicating this “genome organizer” may have a crucial role in the complex gene expression patterns of human cancers by many mechanisms [26], [28]. A recent study by Tu et al .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of SATB1 Is Associated with Biologic Behavior in Human Renal Cell Carcinoma

et al. 2014

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Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of SATB1 in RCC remains unclear. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of SATB1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of SATB1 was significantly associated with depth of invasion (P<0.001), lymph node status (P = 0.001) and TNM stage (P = 0.009). SATB1 knockdown inhibited the proliferation, migration and invasion of 786-O cells, whereas SATB1 overexpression promoted the growth and aggressive phenotype of ACHN cells in vitro. Furthermore, SATB1 expression was positively correlated with ZEB2 expression (P = 0.013), and inversely linked to levels of SATB2 and E-cadherin (P = 0.005 and P<0.001, respectively) in ccRCC tissues. Our data provide a basis for the concept that overexpression of SATB1 may play a critical role in the acquisition of an aggressive phenotype for RCC cells through EMT, providing new insights into the significance of SATB1 in invasion and metastasis of ccRCC, which may contribute to fully elucidating the exact mechanism of development and progression of RCC.

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“…While initial studies provided controversial results on the role of PML in regulation of MHC-I expression (65)(66)(67)(68), more-recent data convincingly demonstrated that PML acts as a positive regulator of IFN-␥-induced MHC-II expression. Attempts to elucidate the mechanistic basis of this activity revealed that PML induces activation and DNA binding of STAT1 immediately after IFN induction, thereby enhancing transcription of genes such as the MHC-II transactivator (CIITA) (44,45).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

Scherer

Otto

Stump

et al. 2016

J Virol

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PML is the organizer of cellular structures termed nuclear domain 10 (ND10) or PML-nuclear bodies (PML-NBs) that act as key mediators of intrinsic immunity against human cytomegalovirus (HCMV) and other viruses. The antiviral function of ND10 is antagonized by viral regulatory proteins such as the immediate early protein IE1 of HCMV. IE1 interacts with PML through its globular core domain (IE1 CORE ) and induces ND10 disruption in order to initiate lytic HCMV infection. Here, we investigate the consequences of a point mutation (L174P) in IE1 CORE , which was shown to abrogate the interaction with PML, for lytic HCMV infection. We found that a recombinant HCMV encoding IE1-L174P displays a severe growth defect similar to that of an IE1 deletion virus. Bioinformatic modeling based on the crystal structure of IE1 CORE suggested that insertion of proline into the highly alpha-helical domain severely affects its structural integrity. Consistently, L174P mutation abrogates the functionality of IE1 CORE and results in degradation of the IE1 protein during infection. In addition, our data provide evidence that IE1 CORE as expressed by a recombinant HCMV encoding IE1 1-382 not only is required to antagonize PML-mediated intrinsic immunity but also affects a recently described function of PML in innate immune signaling. We demonstrate a coregulatory role of PML in type I and type II interferon-induced gene expression and provide evidence that upregulation of interferon-induced genes is inhibited by IE1 CORE . In conclusion, our data suggest that targeting PML by viral regulatory proteins represents a strategy to antagonize both intrinsic and innate immune mechanisms. IMPORTANCEPML nuclear bodies (PML-NBs), which represent nuclear multiprotein complexes consisting of PML and additional proteins, represent important cellular structures that mediate intrinsic resistance against many viruses, including human cytomegalovirus (HCMV). During HCMV infection, the major immediate early protein IE1 binds to PML via a central globular domain (IE1 CORE ), and we have shown previously that this is sufficient to antagonize intrinsic immunity. Here, we demonstrate that modification of PML by IE1 CORE not only abrogates intrinsic defense mechanisms but also attenuates the interferon response during infection. Our data show that PML plays a novel coregulatory role in type I as well as type II interferon-induced gene expression, which is antagonized by IE1 CORE . Importantly, our finding supports the view that targeting of PML-NBs by viral regulatory proteins has evolved as a strategy to inhibit both intrinsic and innate immune defense mechanisms. H uman cytomegalovirus (HCMV), a member of the ␤-subgroup of herpesviruses, is a widespread human pathogen of high clinical relevance that can cause life-threatening diseases in newborns and people with compromised immune system such as AIDS, transplantation, or malignancy patients. The lytic replication cycle of HCMV is characterized by three sequential phases of viral gene expression, te...

show abstract

Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus

Cited by 208 publications

References 44 publications

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

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

Overexpression of SATB1 Is Associated with Biologic Behavior in Human Renal Cell Carcinoma

Characterization of Recombinant Human Cytomegaloviruses Encoding IE1 Mutants L174P and 1-382 Reveals that Viral Targeting of PML Bodies Perturbs both Intrinsic and Innate Immune Responses

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