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Investigating the topography of nuclear phosphoinositide signalling in relation to chromatin and the genome

Objective

Phosphoinositides (PIs) are an important group of phospholipid messengers that regulate diverse cellular functions. A combination of mono, bis and tris-phosphorylation generates seven different PIs present in various subcellular compartments and importantly found within the nucleus. Nuclear PI levels change in response to diverse stimuli such as differentiation, growth factor receptor activation, growth responses in vivo, cell cycle progression, DNA damage, and cellular stressors. Chromatin forms a highly ordered repressive structure that limits access to the DNA sequence. It is widely held that disruption of chromatin compaction, which can be induced by histone tail modification is a rate-determining step in processes such as RNA transcription, DNA replication and DNA repair. Histones modification is reversible and its homeostasis is maintained by antagonistic enzymes that modify (writers) and those that remove the modification (erasers), while proteins that interact with the modifications (readers) act to interpret them. Differential states of histone modification appear to exhibit distinct distribution patterns in mammalian chromatin and appear to define different transcriptional landscapes. We have shown that many proteins that act as writers, readers and erasers of histone marks such as PHD finger containing proteins are receptors for nuclear PIs, suggesting a role for nuclear PI in chromatin modulation. In this study I will develop and use novel technologies and proprietary specific small molecular weight inhibitors of PI-kinases, to define the topographical environment of nuclear PI-signalling in relation to different chromatin landscapes and the genome. I will then determine if and how specific modulation of nuclear PIs in different chromatin landscapes functionally regulates transcriptional output. I expect to uncover a novel regulatory layer of chromatin modulation that depends on changes in nuclear PIs induced by extra and intra cellular cues.

Field of science

  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /natural sciences/physical sciences/astronomy/planetary science/planetary geology
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

FONDAZIONE ISTITUTO NAZIONALE DI GENETICA MOLECOLARE INGM
Address
Via Francesco Sforza 35
20122 Milano
Italy
Activity type
Research Organisations
EU contribution
€ 249 242,80
Administrative Contact
Stefano Apollonio (Mr.)