Hi-C Techniques Timeline (Explained Simply)
Here's the complete timeline of Hi-C sequencing techniques from top journals, explained in the simplest way possible:
| Year | Technique | Type | What Makes It Different | Journal |
|---|---|---|---|---|
| 2009 | Hi-C (original) | Bulk | First genome-wide method - crosslinks DNA with formaldehyde, cuts with restriction enzyme, ligates nearby fragments, sequences everything [1][2] | Science |
| 2014 | in situ Hi-C | Bulk | Does ligation INSIDE the nucleus (not in solution) - less noise, needs fewer cells (2-5M vs 20M), faster (3 days vs 7 days) [3][4] | Cell |
| 2015 | Micro-C | Bulk | Uses MNase enzyme instead of restriction enzyme - cuts DNA at nucleosome level for super high resolution [5] | Nature Methods |
| 2017 | scHi-C (Nagano) | Single-cell | First single-cell version - uses MboI enzyme, biotin labeling, PCR amplification per cell (~225k contacts/cell) [5][6] | Genome Research |
| 2017 | scHi-C (Stevens) | Single-cell | Uses AluI enzyme (makes blunt cuts) and lyses cells before digestion - higher quality ratios (~61k contacts/cell) [5] | Nature |
| 2017 | snHi-C | Single-nucleus | Isolates NUCLEI first before fixation - cleaner signal, best for frozen samples (~187k contacts/cell) [5] | Nature |
| 2017 | sci-Hi-C | Single-cell | Uses combinatorial barcoding like a barcode factory - no need to physically separate cells, can process thousands at once (~5,500 contacts/cell) [5][7] | Science |
| 2017 | Dip-C | Single-cell | Separates mom and dad chromosomes (haplotypes) - uses META amplification instead of PCR (~252-365k contacts/cell) [5] | Science |
| 2018 | scNanoHi-C | Single-cell | Uses long-read nanopore sequencing instead of short reads - can see longer range interactions (~800k contacts/cell) [5] | Nature Protocols |
| 2019 | sn-m3C-seq | Single-cell multi-omics | Does Hi-C AND reads DNA methylation marks at same time using bisulfite treatment (~845k contacts/cell) [5] | Nature Methods |
| 2019 | scMethyl Hi-C | Single-cell multi-omics | Captures chromatin contacts AND methylation together with biotinylated filling (~78k contacts/cell) [5] | Nature Methods |
| 2019 | scSPRITE | Single-cell | No physical cell separation needed - 3 nucleus barcodes + 3 spatial barcodes, only labels DNA ends (~177k contacts/cell) [5] | Nature Genetics |
| 2021 | s3-GCC | Single-cell multi-omics | Combines Hi-C + whole genome sequencing together - best consistency in measurements (~1.2M contacts/cell) [5] | Nature Biotechnology |
| 2023 | HiRES | Single-cell multi-omics | Does Hi-C + RNA-seq at the same time - reverse transcribes RNA before cutting chromatin (~280k contacts/cell) [5][8] | Science |
| 2024 | MUSIC | Single-cell multi-omics | Does THREE things at once: Hi-C + RNA-seq + RNA-DNA contacts in same cell (~84k contacts/cell) [5] | Nature |
| 2024 | Droplet Hi-C | Single-cell | Uses 10x Genomics droplet platform - super fast (10 hours), can do 40,000+ cells at once [9][5] | Nature Biotechnology |
| 2025 | dscHi-C-multiome | Single-cell multi-omics | Droplet-based Hi-C + RNA-seq together in one experiment using microfluidics [10] | Cell Discovery |
Simple Summary
Only 3 are bulk methods (Hi-C original, in situ Hi-C, Micro-C) - these study millions of cells mixed together. The other 14 are single-cell or single-nucleus methods - these look at one cell at a time to see how each individual cell is different.[1][2][3][6][5]
The evolution went from measuring lots of cells together (2009-2015) to measuring individual cells (2017 onwards), and now we can measure multiple things in the same cell simultaneously like chromatin structure + RNA + methylation. The newest droplet-based methods can process tens of thousands of cells in just 10 hours, making it much faster and cheaper than before.[5][9][10]
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