PU.1 ANTISENSE

ROLE OF ANTISENSE RNAs ON PU.1 REGULATION AND HEMATOPOIESIS

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 Obiettivo del progetto (Objective)

'PU.1 levels are critical for normal hematopoiesis and, even modest alterations can lead to leukemia and lymphoma. To achieve optimal expression of the PU.1 gene at different stages of hematopoiesis, multiple interactions are required between its regulatory elements to form fine chromatin architecture. While significant advances have been made in understanding which PU.1 locus chromatin states are active or silent, nothing is known how these states are propagated and maintained. The overall goal of the proposed project is to understand the role of antisense RNAs in the regulation of the PU.1 gene. Therefore I will (1) Characterize the timing, order, cellular localization, and levels of the natural noncoding antisense and coding PU.1 transcripts and formation of the active chromatin architecture within the PU.1 gene locus during cell development; (2) Investigate the functional effect of nuclear ablation of antisense concoding RNAs ablation on the formation of the active chromatin configuration and the expression of the PU.1 gene and, ultimately, on hematopoietic stem cell (HSC) fate; (3) Study the functional role of antisense noncoding RNAs in tissue culture and transgenic systems; and (4) Investigate the functional connection between the expression of the antisense noncoding RNAs and the occurrence of the other epigenetic marks, such as chromatin compaction, covalent histone modification, and DNA methylation. Accomplishment of these aims will enable us to understand the roles of antisense noncoding RNAs corresponding to PU.1 gene locus in the regulation of hematopoietic stem cell differentiation and to identify naturally occurring RNAmediated regulatory mechanisms, the manipulation of which might lead to critical changes in cell fate and provide knowledge of how changes in antisense RNAs can lead to disorders of hematopoietic stem cell function and leukemia.'

Introduzione (Teaser)

Haematopoiesis is the process of generating all cells in the blood from common progenitor or stem cells. European researchers are shedding light onto the molecular regulation of this process.

Descrizione progetto (Article)

A well-orchestrated and tightly regulated process, haematopoiesis involves the activity of many transcription factors that work to activate differentiation-specific genes. The transcription factor PU.1 is expressed early on during haematopoiesis and is essential for normal myeloid development. Reduced expression of PU.1 leads to the development of acute myeloid leukaemia, a group of disorders associated with an aberrant accumulation of immature precursor cells that fail to differentiate.

Understanding the regulation of PU.1 expression is, therefore, relevant for both normal and pathological haematopoiesis. In this context, the EU-funded 'Role of antisense RNAs on PU.1 regulation and hematopoiesis' (PU.1 ANTISENSE) project proposes to investigate the role of non-coding antisense RNAs in the regulation of PU.1 expression and haematopoietic stem cell differentiation.

Non-coding antisense RNAs are emerging as a new component of the transcriptional regulation machinery, and can also participate in post-transcriptional modifications and epigenetic regulation. The transcriptional regulation by non-coding antisense RNAs is facilitated through their binding to normal gene transcripts, a process that generates double-stranded RNA molecules, which eventually get degraded by the cell.

The study aims to identify the natural non-coding antisense molecules that correspond to the PU.1 gene locus and elucidate when, where and how they are generated with respect to coding PU.1 transcripts. Researchers will ablate these non-coding RNAs and assess the impact on chromatin configuration, on epigenetic marks and on expression of the PU.1 gene. This information will be linked to functional studies regarding haematopoietic stem cell differentiation.

Manipulation of such RNA-mediated regulatory processes has the potential to alter cell fate and thus could be exploited therapeutically. Importantly, the findings of the PU.1 ANTISENSE study should help delineate how changes in antisense RNA molecules can lead to disorders of haematopoietic stem cell function and leukaemia.