Elucidating the importance and regulation of key enhancers for human MEIS1 expression

Abstract

Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.

High Density Domain-Focused CRISPR Screens Reveal Novel Epigenetic Regulators ofHOX/MEISActivation in Acute Myeloid Leukemia

“…S1A). We used a CALM-AF10 positive AML cell line – U937 - where the enhanced green fluorescence protein (eGFP) is knocked into the endogenous MEIS1 locus immediately upstream of the start codon 14 . Leveraging this system, we sought to comprehensively identify epigenetic regulators of MEIS1 expression as a surrogate for identifying HOX/MEIS regulators.…”

“…We reasoned that a detailed and systematic identification of epigenetic modulators critical for sustaining HOX/MEIS-activation in AML would help identify novel nodes for targeted drug-discovery campaigns aimed at this clinically important pathway. To this end, we conducted pharmacological and CRISPR-based genetic screens using enhanced green fluorescence protein (eGFP) tagged MEIS1 AML cells 14 . Our screens identified several novel regulators of HOX/MEIS expression in AML and many of them were important for sustaining the expression of an array of leukemia oncogenes that drive AML including BMI1, SATB1 and MYC .…”

The impact of MEIS1 TALE homeodomain transcription factor knockdown on glioma stem cell growth

“…MEIS1 plays a crucial role in cellular development and proliferation (Li et al 2022 ). The MEIS1 locus covers around 175 kb of the genome containing several regulatory domains and enhancers (Xiang et al 2022 ). MEIS1 expression has been linked as an oncogene by regulating the proliferation of acute myeloid leukemia (Li et al 2016 ; Xiang et al 2022 ) and prostate cancer (Johng et al 2019 ), migration in pancreatic cancer (von Burstin et al 2017 ), and stemness and epithelial-mesenchymal transition (EMT) capability in esophageal squamous cell carcinoma (Mahmoudian et al 2019 ; Zargari et al 2020 ).…”

“…The MEIS1 locus covers around 175 kb of the genome containing several regulatory domains and enhancers (Xiang et al 2022 ). MEIS1 expression has been linked as an oncogene by regulating the proliferation of acute myeloid leukemia (Li et al 2016 ; Xiang et al 2022 ) and prostate cancer (Johng et al 2019 ), migration in pancreatic cancer (von Burstin et al 2017 ), and stemness and epithelial-mesenchymal transition (EMT) capability in esophageal squamous cell carcinoma (Mahmoudian et al 2019 ; Zargari et al 2020 ). Conversely, its expression suppresses colorectal (Li et al 2022 ), prostate (Bhanvadia et al 2018 ; VanOpstall et al 2020 ; Whitlock et al 2020 ), lung (Li et al 2014 ), and esophageal (Rad et al 2016 ) cancers.…”

MEIS1 Is a Common Transcription Repressor of the miR-23a and NORHA Axis in Granulosa Cells

“…The purpose of this study was to elucidate the common modulators of miR-23a and NORHA axis in porcine GCs to understand the molecular regulation. We identified MEIS1, an important member of the TALE (transcription activator-like effectors) protein family and a transcription factor of key genes related to various physiological and pathological processes [ 13 , 14 , 15 , 16 ], as a common transcription factor of the miR-23a and NORHA axis in GCs. Furthermore, we also showed that transcription factor MEIS1 forms a small regulatory network with the miR-23a/NORHA axis by inhibiting their transcription, which further inhibits GC apoptosis.…”