ENL: structure, function, and roles in hematopoiesis and acute myeloid leukemia

Zhou, Jianbiao; Ng, Yan Ling; Chng, Wee‐Joo

doi:10.1007/s00018-018-2895-8

Cited by 18 publications

(15 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For all these transcription factors, only one significant binding event (MLLT1) was detected surrounding methylated ZBTB33 binding sites in both cell lines (Figure 3 left). Interestingly, MLLT1, also known as ENL, is a critical component of the super elongation complex and also a histone acetylation reader [27]. The co-occupancy of MLLT1 with ZBTB33 in methylated binding sites suggests the potential of transcriptional regulation in these regions.…”

Section: Co-occupancy Of Transcription Factors Surrounding Zbtb33 Binmentioning

confidence: 99%

ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin

Lin

Rebbani

Jha

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: ZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA. Although these dual binding preferences enable ZBTB33 to function as an active as well as repressive regulator of gene expression, little is known about the underlining molecular mechanisms. Results: In this study, we aimed to investigate the role of ZBTB33 as a methylated DNA binding factor. We took advantage of the latest releases of the ENCODE sequencing datasets, including ZBTB33 ChIPseq, whole genome bisulfite sequencing (WGBS), histone mark ChIP-seq and sequencing assays determining the chromatin states, to characterize the chromatin landscapes surrounding methylated ZBTB33 binding sites. Interestingly, our integrative analyses demonstrated that the majority of methylated ZBTB33 binding sites were located within condensed chromatin, which are inaccessible to DNase I and Tn5 transposase. Moreover, these sites were carrying a newly revealed histone post-translational modification signature, with significant enrichment of mono-methylation at lysine 4 of histone 3 (H3K4me1) and a complete absence of other active or expected repressive histone marks. Conclusions: Overall, our analyses revealed that ZBTB33 has the unique ability to bind methylated DNA across heterochromatin in a transition state, suggesting a potential role for ZBTB33 in heterochromatin priming. KeywordsKaiso, DNA methylation, H3K4me1, primed heterochromatin 3 Background ZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. Similar to DNA (cytosine-5)-methyltransferase 1 (DNMT1) depletion, ZBTB33 knockdown phenotypes in Xenopus embryos include precocious activation of gene expression, apoptosis and developmental arrest [1].Likewise, ZBTB33 depletion in the K562 cell line inhibits granulocyte differentiation and promotes cell proliferation [2]. In mammals, though, ZBTB33-knockout mice lack any significant phenotypes [3,4]; the depletion of ZBTB33 leads to intestinal tumorigenesis resistance [3], splenomegaly [4], increased locomotion and reduced volume of the lateral ventricles [5].Like other BTB/POZ proteins, ZBTB33 forms a homodimer or heterodimer via its highly conserved BTB/POZ domains [6,7]. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA [8,9], which allows ZBTB33 to act as an activator or repressor of gene expression. In many types of cancer cells, ZBTB33 methyl-CpG-dependent binding events in the proximal promoters of essential tumor suppressor genes, such as Cyclin-dependent kinase inhibitor 2a (Cdk2a), Hypermethylated in cancer 1 (H1c1) and O-6-methylguanine-DNA methyltransferase (Mgmt) [10], are associated with repressive regulation, suggesting a crucial role in tumorigenesis. Further, ZBTB33 binding activity within the methylated promoter of E-cadherin is associated with E-cadherin silencing and an increase in canc...

show abstract

Section: Co-occupancy Of Transcription Factors Surrounding Zbtb33 Binmentioning

confidence: 99%

ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin

Lin

Rebbani

Jha

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…An epigenetic upregulation of FKBP5 could promote NF-kB activation [ 30 ]. STAT3-NFkB activity is involved in chemoresistance in MM cells [ 31 ], and NFkB was shown to be constitutively active as a result of asbestos-induced chronic inflammation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The MLLT1 gene encodes the ENL protein, a histone acetylation reader component of the super elongation complex (SEC), which promotes transcription at the elongation stage by suppressing transient pausing by the polymerase at multiple sites along the DNA. In acute myeloid leukemia, MLLT1 regulates chromatin remodeling and gene expression of many important proto-oncogenes [ 31 ]. Yoshikawa and colleagues suggested that mesothelioma may be the consequence of the somatic inactivation of chromatin-remodeling complexes and/or histone modifiers, including MLLT1 [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment

Cugliari

Allione

Russo

et al. 2021

Cancers

View full text Add to dashboard Cite

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

show abstract

“…[44] Another intermediary, MLLT1 is a component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. [45] Kruppel-like factor 9 (KLF9), a TF, is critical for the inhibition of growth and development of tumors. KLF9 role is notable in lung and pancreas tumors.…”

Section: Discussionmentioning

confidence: 99%

Study on mRNA expression of Cajal body – Gemini of coiled body proteins in head and neck squamous cell carcinoma

Thavarajah

Imaneul

Joshua

et al. 2020

IJMIO

View full text Add to dashboard Cite

Objectives: The role of proteins of Cajal bodies (CB) and its identical twin, Gemini of coiled bodies (GEMs) in maintaining genomic integrity and its influence on the initiation, progression, and prognosis of head and neck squamous cell carcinoma (HNSCC) is gaining attention. We attempted to identify the CB and GEM-associated proteins (CB-GEMs) expression in HNSCC patients and study the influence of gender, TP53 mutation, age, and tobacco use on such expression. Material and Methods: TP53 mutation, tobacco use, gender, and mRNA levels of CB-GEM proteins of 520 HNSCC cases were collected and subjected to differential expression (DE) analysis. The resultant DE genes were used to create a transcriptional factor gene network using encode chip sequential data. Pathway analysis of the network was performed and presented. P ≤ 0.05 was taken as significant. Results: For smoking, the genes GEMIN8, FMR1, TRIM22, and FBL emerged as significantly DE genes. For gender, EAF1, GEMIN8, ZC3H8, TRIM22, FBL, LSG1, ZNF473, GMNC, GEMIN2, ISG20, Opa interacting protein 5, GMNN, and CDK2 were DE gene with statistical significance. For TP53, 15 genes were DE with statistical significance. Transcriptional misregulation in cancer was the frequently affected pathway. The CB-GEM bodies are effective highly conserved, splicesomal organelles that are needed for proper mRNA assembly. Certain mRNA of proteins of the CB-GEM bodies is influenced by TP53 status, gender, and tobacco use. Conclusion: The DE of CB-GEM bodies related protein in HNSCC patients are presented. Furthermore, we identified certain critical pathways, where the DE genes of CB-GEM bodies exert critical influence on HNSCC characteristics. This could potentially alter the HNSCC progression, treatment response, and prognosis.

show abstract

ENL: structure, function, and roles in hematopoiesis and acute myeloid leukemia

Cited by 18 publications

References 74 publications

ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin

ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment

Study on mRNA expression of Cajal body – Gemini of coiled body proteins in head and neck squamous cell carcinoma

Contact Info

Product

Resources

About