The cohesin protein complex holds sister chromatids in dividing cells together 
and is essential for chromosome segregation. Recently, cohesin has been 
implicated in mediating transcriptional insulation, via its interactions with 
CTCF. Here, we show in different cell types that cohesin functionally behaves as 
a tissue-specific transcriptional regulator, independent of CTCF binding. By 
performing matched genome-wide binding assays (ChIP-seq) in human breast cancer 
cells (MCF-7), we discovered thousands of genomic sites that share cohesin and 
estrogen receptor alpha (ER) yet lack CTCF binding. By use of human 
hepatocellular carcinoma cells (HepG2), we found that liver-specific 
transcription factors colocalize with cohesin independently of CTCF at 
liver-specific targets that are distinct from those found in breast cancer 
cells. Furthermore, estrogen-regulated genes are preferentially bound by both ER 
and cohesin, and functionally, the silencing of cohesin caused aberrant re-entry 
of breast cancer cells into cell cycle after hormone treatment. We combined 
chromosomal interaction data in MCF-7 cells with our cohesin binding data to 
show that cohesin is highly enriched at ER-bound regions that capture 
inter-chromosomal loop anchors. Together, our data show that cohesin cobinds 
across the genome with transcription factors independently of CTCF, plays a 
functional role in estrogen-regulated transcription, and may help to mediate 
tissue-specific transcriptional responses via long-range chromosomal 
interactions.