LRF Promotes Indirectly Advantageous Chromatin Conformation via BGLT3-lncRNA Expression and Switch from Fetal to Adult Hemoglobin

Vasiliki Chondrou; Athanasios-Nasir Shaukat; Georgios Psarias; Katerina Athanasopoulou; Evanthia Iliopoulou; Ariadne Damanaki; Constantinos Stathopoulos; Argyro Sgourou

doi:10.20944/preprints202205.0364.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 25 May 2022 / Approved: 26 May 2022 / Online: 26 May 2022 (10:39:49 CEST)

Hemoglobin switch from fetal (HbF) to adult (HbA) has been studied intensively as an essential model for gene’s expression regulation, but also as a beneficial therapeutic approach for β-hemoglobinopathies, towards the objective of reactivating HbF. Transcription factor LRF (Leukemia/lymphoma-related), encoded from ZBTB7A gene has been implicated in fetal hemoglobin silencing, though has a wide range of functions that have not been fully clarified. We thus established LRF/ZBTB7A-overexpressing and ZBTB7A-knockdown K562 (human erythroleukemia cell line) clones and hemoglobin production was evaluated pre- and post-induction. Related effects on the process of hemoglobin switch from fetal to adult were also assessed. Transgenic K562 clones were further developed and studied under the influence of epigenetic chromatin regulators, such as DNA methyl transferase 3 (DNMT3) and Histone Deacetylase 1 (HDAC1), to evaluate LRF’s potential disturbance upon aberrant epigenetic background and provide valuable information of the preferable epigenetic frame, in which LRF unfolds its action on the β-type globin’s expression. ChIP-seq analysis demonstrated that LRF binds το γ-globin genes (HBG2/1) and apparently associates BCL11A for their silencing, but also, during erythropoiesis induction LRF binds BGLT3 gene promoting BGLT3-lncRNA production through the γ-δ intergenic region of β-type globin’s locus, triggering the transcriptional events from γ- to β-globin switch.

Hemoglobin switch; BGLT3-lncRNA expression; chromatin conformation; LRF/ZBTB7A overexpression

LIFE SCIENCES, Molecular Biology

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LRF Promotes Indirectly Advantageous Chromatin Conformation via BGLT3-lncRNA Expression and Switch from Fetal to Adult Hemoglobin

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