Abstract:
Thymus is one of the primary lymphoid organs and its epithelial cells hosts a phenomenon,
promiscuous gene expression, through which all the peripheral transcripts of
the body are ectopically expressed as self-antigens in them. The functional role of thymus
is further extended to thymocytes, which on their course of development interacts
with self-antigens through surface borne T cell receptors and co-receptors. The affinity
of this interaction is monitored closely and in later stages of development, if it crosses
a threshold, corresponding thymocytes either succumb to apoptosis or transform into
thymic T regulatory cells by expressing Foxp3. Either fate fundamentally deals with
autoimmunity and its prevention. The following study focuses on regulatory control of
pGE; at transcriptional and chromatin configurational levels. For the purpose, contextspecific
accessibility and transcriptomic datasets were combined to obtain regulatory
element (RE), transcription factor (TF) and chromatin regulator (CR); responsible for
regulatory control of each individual target gene (TG); by running a statistical model,
termed as, Paired Expression and Chromatin Accessibility model. Building and observing
a CR-TF-RE-TG regulatory network revealed a lot of interesting and novel
information. The found TFs belong to various families, members of which have been
mentioned in literature in relation to pGE. Most of the REs, as enhancers, were far away
from the transcription start sites; from 10 kb to 1 Mb. These enhancers were involved
in long range intra-chromosomal interactions with other enhancers and promoters. Furthermore,
these interactions generally extended their control on distant genes, situated
around 40-50 kb from them. Permissive histone marks, comparatively to repressive
ones, were found more prevalent at the REs. Chromatin looping as a probable cause
of these interactions were observed by looking into associated CRs and their modifications.
Acetylation and deacetylation appeared as the main agents of post-transcriptional
chromatin modification. The other observed modifications dealt with nucleosome positioning
and permissive H3K4me3. The study recapitulates some of the regulatory
relations mentioned in literature and offers new possibilities for future endeavours.
