TADMAN: a tool designed for identifying novel cell fate transition regulators

TADMAN algorithm: A New Algorithm that Integrates TAD Reorganization-based Multiomics Analysis to Identify the Reprogramming Regulators
The reprogramming regulators could be identified by integrating TAD reorganization-based Multiomics Analysis (TADMAN). TADMAN filters SE-related genes with muiltiomics analysis to get the reprogramming regulator candidates, including HiC, OCT4 HiChIP, OCT4 ChIP-Seq and RNA-Seq. TADMAN stipulates that the genes encoding the regulators should meet the following criteria: 1) they are regulated by SEs in reorganized TAD (HiC); 2) the NRR genes and SEs are connected by OCT4 loops (OCT4 HiChIP); 3) both SEs and their target genes are occupied by OCT4 peaks (OCT4 ChIP-seq); and 4) the genes are the top 10% highly expressed genes at any stage of reprogramming and showed at least 10-fold change in expression compared to the previous or next stage (RNA-seq). Taken together, if a SE-related gene would be considered as a regulator candidate by TADMAN, it should locate in reorganized TAD, interact with SE by OCT4 loops, be occupied by OCT4, and highly expressed.

(A) Scheme for TADMAN, which was used to identify reprogramming regulators. The model comprises four conditions: (1) in situ Hi-C, the encoding genes of the regulators are regulated by SEs in reorganized TADs; (2) HiChIP, OCT4 loops link the encoding genes of the regulators with SEs; (3) ChIP-seq, the SEs and the encoding genes are co-occupied by OCT4 peaks; and (4) RNA-seq: the encoding genes are the top 10% of the highly expressed genes at any stage of reprogramming and are at least 10-fold change of expression from the previous or next stage.

(B) Heatmap showing the dynamic expression of the 59 candidate reprogramming regulators by TADMAN during reprogramming (left). According to the expression profile, the candidates are divided into four groups, in which groups 1–3 are composed of the candidates with upregulated expressions during reprogramming, whereas group 4 is composed of the candidates with downregulated expressions (right). Asterisk stands for the 26 randomly selected candidates for functional validation in this study.

(C and D) The reprogramming efficiency is evaluated by iPSC colony formation assay. After 12 days of reprogramming, the iPSC colonies of each knockdown (KD) test are stained by alkaline phosphatase (C). Both colony number (compared with shEV) and p value (p < 0.05) were considered for significance analysis (D). The candidates in group 4 (marked with a dotted line box) were not effectively validated. The area on the right of the vertical red dotted line means that the iPSC colony number is more than that of the control. The area above the horizontal red dotted line is p < 0.05 as compared with that of the control. iPSC colony numbers at day 12 of reprogramming are from three biological replicates.

Cite

Cite our paper by

@article {Wang2021multiscale,
	author = {Jia Wang, Haopeng Yu},
	title = {TADMAN: A new algorithm that integrates TAD reorganization-based multiomics analysis to identify the reprogramming regulators},
	year={2021},
	publisher = {Nature Publishing Group},
	journal = {Under Submited}
}

Availability
https://github.com/corephi/TADMAN

Please contact

o.sj@live.com or raise an issue in the github repo with any questions about installation or usage.